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Sample records for adaptive immune mechanisms

  1. Subverting the adaptive immune resistance mechanism to improve clinical responses to immune checkpoint blockade therapy

    PubMed Central

    Kim, Young J

    2015-01-01

    The correlation between tumor-infiltrating lymphocyte (TIL)-expression of programmed cell death ligand 1 (PD-L1) and clinical responsiveness to the PD-1 blocking antibody nivolumab implicates adaptive immune evasion mechanisms in cancer. We review our findings that tumor cell PD-L1 expression is induced by interferon γ (IFNγ) producing TILs. We provide a mechanistic rationale for combining IFNγ+ T helper type 1 (Th1)-inducing cancer vaccines with PD-1 immune checkpoint blockade. PMID:25964860

  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. Brucella evasion of adaptive immunity.

    PubMed

    Martirosyan, Anna; Gorvel, Jean-Pierre

    2013-02-01

    The complex immune system of mammals is the result of evolutionary forces that include battles against pathogens, as sensing and defeating intruders is a prerequisite to host survival. On the other hand, microorganisms have evolved multiple mechanisms to evade both arms of immunity: the innate and the adaptive immune systems. The successful pathogenic intracellular bacterium Brucella is not an exception to the rule: Brucella displays mechanisms that allow evasion of immune surveillance in order to establish persistent infections in mammals. In this review, we highlight some key mechanisms that pathogenic Brucella use to evade the adaptive immune system.

  4. 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.

  5. Adaptive Immunity to Fungi

    PubMed Central

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

    2015-01-01

    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. PMID:25377140

  6. Adaptive Immunity Against Staphylococcus aureus.

    PubMed

    Karauzum, Hatice; Datta, Sandip K

    2016-02-27

    A complex interplay between host and bacterial factors allows Staphylococcus aureus to occupy its niche as a human commensal and a major human pathogen. The role of neutrophils as a critical component of the innate immune response against S. aureus, particularly for control of systemic infection, has been established in both animal models and in humans with acquired and congenital neutrophil dysfunction. The role of the adaptive immune system is less clear. Although deficiencies in adaptive immunity do not result in the marked susceptibility to S. aureus infection that neutrophil dysfunction imparts, emerging evidence suggests both T cell- and B cell-mediated adaptive immunity can influence host susceptibility and control of S. aureus. The contribution of adaptive immunity depends on the context and site of infection and can be either beneficial or detrimental to the host. Furthermore, S. aureus has evolved mechanisms to manipulate adaptive immune responses to its advantage. In this chapter, we will review the evidence for the role of adaptive immunity during S. aureus infections. Further elucidation of this role will be important to understand how it influences susceptibility to infection and to appropriately design vaccines that elicit adaptive immune responses to protect against subsequent infections.

  7. Adaptive immune resistance: How cancer protects from immune attack

    PubMed Central

    Ribas, Antoni

    2015-01-01

    Adaptive immune resistance is a process where the cancer changes its phenotype in response to a cytotoxic or pro-inflammatory immune response, thereby evading it. This adaptive process is triggered by the specific recognition of cancer cells by T cells, which leads to the production of immune-activating cytokines. Cancers then hijack mechanisms developed to limit inflammatory and immune responses and protect themselves from the T cell attack. Inhibiting adaptive immune resistance is the mechanistic basis of responses to PD-1 or PD-L1 blocking antibodies, and may be of relevance for the development of other cancer immunotherapy strategies. PMID:26272491

  8. Inflammatory bowel disease related innate immunity and adaptive immunity.

    PubMed

    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.

  9. Filoviral immune evasion mechanisms.

    PubMed

    Ramanan, Parameshwaran; Shabman, Reed S; Brown, Craig S; Amarasinghe, Gaya K; Basler, Christopher F; Leung, Daisy W

    2011-09-01

    The Filoviridae family of viruses, which includes the genera Ebolavirus (EBOV) and Marburgvirus (MARV), causes severe and often times lethal hemorrhagic fever in humans. Filoviral infections are associated with ineffective innate antiviral responses as a result of virally encoded immune antagonists, which render the host incapable of mounting effective innate or adaptive immune responses. The Type I interferon (IFN) response is critical for establishing an antiviral state in the host cell and subsequent activation of the adaptive immune responses. Several filoviral encoded components target Type I IFN responses, and this innate immune suppression is important for viral replication and pathogenesis. For example, EBOV VP35 inhibits the phosphorylation of IRF-3/7 by the TBK-1/IKKε kinases in addition to sequestering viral RNA from detection by RIG-I like receptors. MARV VP40 inhibits STAT1/2 phosphorylation by inhibiting the JAK family kinases. EBOV VP24 inhibits nuclear translocation of activated STAT1 by karyopherin-α. The examples also represent distinct mechanisms utilized by filoviral proteins in order to counter immune responses, which results in limited IFN-α/β production and downstream signaling.

  10. ADAPTIVE MECHANISMS OF THE IMMUNE SYSTEM IN CHILDREN IN FAR NORTH.

    PubMed

    Ivanova, O N; Argunova, E F; Alekseev, S N; Ystugina, T V; Varfolomeev, A R; Troev, I P; Kononova, I V; Egorova, V E

    2015-01-01

    This article is devoted to the probleme of modern Pediatrics pathology of the immune system in children with complicated viral infections. The aim of this study was to investigate the immune and cytokine status in children with complicated acute respiratory viral infections. The study included 100 children are often ill respiratory virus infections (more than 8 times per year) from age 0 to 7 years, and 30 children with upper respiratory tract infection; no more than 1 time per year-the control group. The standards of indicators developed by the staff of Immunological laboratory Diagnostic center of the Ministry of health of Republic Sakha (Yakutia ) together with the Institute of health of the Republic Sakha (Yakutia). Statistical calculations made on the basis of applied programs "SAS"and "SPSS"In the analysis of contingency tables (estimates of the correlation of the characteristic and evaluation of significance of differences between groups) used the criterion of 2 (Pearson and likelihood ratio and Fisher's exact test. Comparison of mean values was performed univariate analysis of variance using T-student criterion for assessing the equality of mean F-Fisher test to assess equality of variance. Extreme climatic conditions ofthe far North have an impact on immunological mechanisms. In the analysis of changes ofthe immune status revealed the greatest decline in T-cell level and components of complement in children with complications of viral respiratory infections. In children with complicated respiratory viral infections reduced cellular immunity (CD3+, CD41, CD81, CD+, CD 22+). In children with complicated respiratory viral infections decrease levels ofcytokines (IFN-y FN0-d), indicating about the risk of the formation of complications of respiratory viral infections. As a result of drug therapy of broncho-vaxom marked improvement in immune status and the absence of recurrence of respiratory viral infections within the next 3 months after therapy.

  11. Adaptive immunity in the liver

    PubMed Central

    Shuai, Zongwen; Leung, Miranda WY; He, Xiaosong; Zhang, Weici; Yang, Guoxiang; Leung, Patrick SC; Eric Gershwin, M

    2016-01-01

    The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver. PMID:26996069

  12. Bridging innate and adaptive immunity.

    PubMed

    Paul, William E

    2011-12-09

    The Nobel Prize in Physiology or Medicine for 2011 to Jules Hoffmann, Bruce Beutler, and the late Ralph Steinman recognizes accomplishments in understanding and unifying the two strands of immunology, the evolutionarily ancient innate immune response and modern adaptive immunity.

  13. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells.

    PubMed

    Barsoum, Ivraym B; Smallwood, Chelsea A; Siemens, D Robert; Graham, Charles H

    2014-02-01

    Immune escape is a fundamental trait of cancer in which mechanistic knowledge is incomplete. Here, we describe a novel mechanism by which hypoxia contributes to tumoral immune escape from cytotoxic T lymphocytes (CTL). Exposure of human or murine cancer cells to hypoxia for 24 hours led to upregulation of the immune inhibitory molecule programmed cell death ligand-1 (PD-L1; also known as B7-H1), in a manner dependent on the transcription factor hypoxia-inducible factor-1α (HIF-1α). In vivo studies also demonstrated cellular colocalization of HIF-1α and PD-L1 in tumors. Hypoxia-induced expression of PD-L1 in cancer cells increased their resistance to CTL-mediated lysis. Using glyceryl trinitrate (GTN), an agonist of nitric oxide (NO) signaling known to block HIF-1α accumulation in hypoxic cells, we prevented hypoxia-induced PD-L1 expression and diminished resistance to CTL-mediated lysis. Moreover, transdermal administration of GTN attenuated tumor growth in mice. We found that higher expression of PD-L1 induced in tumor cells by exposure to hypoxia led to increased apoptosis of cocultured CTLs and Jurkat leukemia T cells. This increase in apoptosis was prevented by blocking the interaction of PD-L1 with PD-1, the PD-L1 receptor on T cells, or by addition of GTN. Our findings point to a role for hypoxia/HIF-1 in driving immune escape from CTL, and they suggest a novel cancer immunotherapy to block PD-L1 expression in hypoxic-tumor cells by administering NO mimetics.

  14. Immune tolerance induction by integrating innate and adaptive immune regulators

    PubMed Central

    Suzuki, Jun; Ricordi, Camillo; Chen, Zhibin

    2009-01-01

    A diversity of immune tolerance mechanisms have evolved to protect normal tissues from immune damage. Immune regulatory cells are critical contributors to peripheral tolerance. These regulatory cells, exemplified by the CD4+Foxp3+ regulatory T (Treg) cells and a recently identified population named myeloid-derived suppressor cells (MDSCs), regulate immune responses and limiting immune-mediated pathology. In a chronic inflammatory setting, such as allograft-directed immunity, there may be a dynamic “crosstalk” between the innate and adaptive immunomodulatory mechanisms for an integrated control of immune damage. CTLA4-B7-based interaction between the two branches may function as a molecular “bridge” to facilitate such “crosstalk”. Understanding the interplays among Treg cells, innate suppressors and pathogenic effector T (Teff) cells will be critical in the future to assist in the development of therapeutic strategies to enhance and synergize physiological immunosuppressive elements in the innate and adaptive immune system. Successful development of localized strategies of regulatory cell therapies could circumvent the requirement for very high number of cells and decrease the risks associated with systemic immunosuppression. To realize the potential of innate and adaptive immune regulators for the still-elusive goal of immune tolerance induction, adoptive cell therapies may also need to be coupled with agents enhancing endogenous tolerance mechanisms. PMID:19919733

  15. [Advances in molecular mechanisms of adaptive immunity mediated by type I-E CRISPR/Cas system--A review].

    PubMed

    Sun, Dongchang; Qiu, Juanping

    2016-01-04

    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.

  16. 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.

  17. Control of adaptive immunity by the innate immune system

    PubMed Central

    Iwasaki, Akiko; Medzhitov, Ruslan

    2015-01-01

    Microbial infections are recognized by the innate immune system both to elicit immediate defense and to generate long-lasting adaptive immunity. To detect and respond to vastly different groups of pathogens, the innate immune system uses several recognition systems that rely on sensing common structural and functional features associated with different classes of microorganisms. These recognition systems determine microbial location, viability, replication and pathogenicity. Detection of these features by recognition pathways of the innate immune system is translated into different classes of effector responses though specialized populations of dendritic cells. Multiple mechanisms for the induction of immune responses are variations on a common design principle wherein the cells that sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate effector responses. Here we discuss these emerging principles of innate control of adaptive immunity. PMID:25789684

  18. Mechanism of foreign DNA selection in a bacterial adaptive immune system.

    PubMed

    Sashital, Dipali G; Wiedenheft, Blake; Doudna, Jennifer A

    2012-06-08

    In bacterial and archaeal CRISPR immune pathways, DNA sequences from invading bacteriophage or plasmids are integrated into CRISPR loci within the host genome, conferring immunity against subsequent infections. The ribonucleoprotein complex Cascade utilizes RNAs generated from these loci to target complementary "nonself" DNA sequences for destruction, while avoiding binding to "self" sequences within the CRISPR locus. Here we show that CasA, the largest protein subunit of Cascade, is required for nonself target recognition and binding. Combining a 2.3 Å crystal structure of CasA with cryo-EM structures of Cascade, we have identified a loop that is required for viral defense. This loop contacts a conserved three base pair motif that is required for nonself target selection. Our data suggest a model in which the CasA loop scans DNA for this short motif prior to target destabilization and binding, maximizing the efficiency of DNA surveillance by Cascade.

  19. 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

  20. Ion channels in innate and adaptive immunity.

    PubMed

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

    2015-01-01

    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.

  1. Autophagy, Immunity, and Microbial Adaptations

    PubMed Central

    Deretic, Vojo; Levine, Beth

    2009-01-01

    Autophagy adjusts cellular biomass and function in response to diverse stimuli, including infection. Autophagy plays specific roles in shaping immune system development, fueling host innate and adaptive immune responses, and directly controlling intracellular microbes as a cell-autonomous innate defense. As an evolutionary counterpoint, intracellular pathogens have evolved to block autophagic microbicidal defense and subvert host autophagic responses for their survival or growth. The ability of eukaryotic pathogens to deploy their own autophagic machinery may also contribute to microbial pathogenesis. Thus, a complex interplay between autophagy and microbial adaptations against autophagy governs the net outcome of host-microbe encounters. PMID:19527881

  2. Natural innate and adaptive immunity to cancer.

    PubMed

    Vesely, Matthew D; Kershaw, Michael H; Schreiber, Robert D; Smyth, Mark J

    2011-01-01

    The immune system can identify and destroy nascent tumor cells in a process termed cancer immunosurveillance, which functions as an important defense against cancer. Recently, data obtained from numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms. However, the immune system can also promote tumor progression. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. In this review, we discuss the current experimental and human clinical data supporting a cancer immunoediting process that provide the fundamental basis for further study of immunity to cancer and for the rational design of immunotherapies against cancer.

  3. Innate and Adaptive Immunity in Atherosclerosis

    PubMed Central

    Packard, René R. S.; Lichtman, Andrew H.; Libby, Peter

    2010-01-01

    Atherosclerosis, a chronic inflammatory disorder, involves both the innate and adaptive arms of the immune response that mediate the initiation, progression, and ultimate thrombotic complications of atherosclerosis. Most fatal thromboses, which may manifest as acute myocardial infarction or ischemic stroke, result from frank rupture or superficial erosion of the fibrous cap overlying the atheroma, processes that occur in inflammatorily active, rupture-prone plaques. Appreciation of the inflammatory character of atherosclerosis has led to the application of C-reactive protein as a biomarker of cardiovascular risk, and the characterization of the anti-inflammatory and immunomodulatory actions of the statin class of drugs. An improved understanding of the pathobiology of atherosclerosis and further studies of its immune mechanisms provide avenues for the development of future strategies directed toward better risk stratification of patients as well as the identification of novel anti-inflammatory therapies. This review retraces leukocyte subsets involved in innate and adaptive immunity and their contributions to atherogenesis. PMID:19449008

  4. 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...

  5. Immune escape of γ-herpesviruses from adaptive immunity.

    PubMed

    Hu, Zhuting; Usherwood, Edward J

    2014-11-01

    Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are two γ-herpesviruses identified in humans and are strongly associated with the development of malignancies. Murine γ-herpesvirus (MHV-68) is a naturally occurring rodent pathogen, representing a unique experimental model for dissecting γ-herpesvirus infection and the immune response. These γ-herpesviruses actively antagonize the innate and adaptive antiviral responses, thereby efficiently establishing latent or persistent infections and even promoting development of malignancies. In this review, we summarize immune evasion strategies of γ-herpesviruses. These include suppression of MHC-I-restricted and MHC-II-restricted antigen presentation, impairment of dendritic cell functions, downregulation of costimulatory molecules, activation of virus-specific regulatory T cells, and induction of inhibitory cytokines. There is a focus on how both γ-herpesvirus-derived and host-derived immunomodulators interfere with adaptive antiviral immunity. Understanding immune-evasive mechanisms is essential for developing future immunotherapies against EBV-driven and KSHV-driven tumors.

  6. Immune mechanisms of sublingual immunotherapy.

    PubMed

    Jay, David C; Nadeau, Kari C

    2014-11-01

    Sublingual immunotherapy (SLIT) is a well-established allergen-specific immunotherapy and a safe and effective strategy to reorient inappropriate immune responses in allergic patients. SLIT takes advantage of the tolerogenic environment of the oral mucosa to promote tolerance to the allergen. Several clinical studies have investigated the complex interplay of innate and adaptive immune responses that SLIT exploits. The oral immune system is composed of tolerogenic dendritic cells that, following uptake of allergen during SLIT, support the differentiation of T helper cell type 1 (Th1) and the induction of IL-10-producing regulatory T cells. Following SLIT, allergic disease-promoting T helper cell type 2 (Th2) responses shift to a Th1 inflammatory response, and IL-10 and transforming growth factor (TGF)-β production by regulatory T cells and tolerogenic dendritic cells suppress allergen-specific T cell responses. These immune changes occur both in the sublingual mucosa and in the periphery of a patient following SLIT. SLIT also promotes the synthesis of allergen-specific IgG and IgA antibodies that block allergen-IgE complex formation and binding to inflammatory cells, thus encouraging an anti-inflammatory environment. Several of these revealing findings have also paved the way for the identification of biomarkers of the clinical efficacy of SLIT. This review presents the emerging elucidation of the immune mechanisms mediated by SLIT.

  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. 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

  9. 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.

  10. Evolution of adaptive immune recognition in jawless vertebrates.

    PubMed

    Saha, Nil Ratan; Smith, Jeramiah; Amemiya, Chris T

    2010-02-01

    All extant vertebrates possess an adaptive immune system wherein diverse immune receptors are created and deployed in specialized blood cell lineages. Recent advances in DNA sequencing and developmental resources for basal vertebrates have facilitated numerous comparative analyses that have shed new light on the molecular and cellular bases of immune defense and the mechanisms of immune receptor diversification in the "jawless" vertebrates. With data from these key species in hand, it is becoming possible to infer some general aspects of the early evolution of vertebrate adaptive immunity. All jawed vertebrates assemble their antigen-receptor genes through combinatorial recombination of different "diversity" segments into immunoglobulin or T-cell receptor genes. However, the jawless vertebrates employ an analogous, but independently derived set of immune receptors in order to recognize and bind antigens: the variable lymphocyte receptors (VLRs). The means by which this locus generates receptor diversity and achieves antigen specificity is of considerable interest because these mechanisms represent a completely independent strategy for building a large immune repertoire. Therefore, studies of the VLR system are providing insight into the fundamental principles and evolutionary potential of adaptive immune recognition systems. Here we review and synthesize the wealth of data that have been generated towards understanding the evolution of the adaptive immune system in the jawless vertebrates.

  11. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms

    PubMed Central

    Goldberg, Emily L; Romero-Aleshire, Melissa J; Renkema, Kristin R; Ventevogel, Melissa S; Chew, Wade M; Uhrlaub, Jennifer L; Smithey, Megan J; Limesand, Kirsten H; Sempowski, Gregory D; Brooks, Heddwen L; Nikolich-Žugich, Janko

    2015-01-01

    Aging of the world population and a concomitant increase in age-related diseases and disabilities mandates the search for strategies to increase healthspan, the length of time an individual lives healthy and productively. Due to the age-related decline of the immune system, infectious diseases remain among the top 5–10 causes of mortality and morbidity in the elderly, and improving immune function during aging remains an important aspect of healthspan extension. Calorie restriction (CR) and more recently rapamycin (rapa) feeding have both been used to extend lifespan in mice. Preciously few studies have actually investigated the impact of each of these interventions upon in vivo immune defense against relevant microbial challenge in old organisms. We tested how rapa and CR each impacted the immune system in adult and old mice. We report that each intervention differentially altered T-cell development in the thymus, peripheral T-cell maintenance, T-cell function and host survival after West Nile virus infection, inducing distinct but deleterious consequences to the aging immune system. We conclude that neither rapa feeding nor CR, in the current form/administration regimen, may be optimal strategies for extending healthy immune function and, with it, lifespan. PMID:25424641

  12. 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

  13. The origins of vertebrate adaptive immunity

    PubMed Central

    Litman, Gary W.; Rast, Jonathan P.; Fugmann, Sebastian D.

    2010-01-01

    Adaptive immunity is mediated through numerous genetic and cellular processes that generate favourable somatic variants of antigen-binding receptors under evolutionary selection pressure by pathogens and other factors. Advances in our understanding of immunity in mammals and other model organisms are revealing the underlying basis and complexity of this remarkable system. Although the evolution of adaptive immunity has been considered to occur by acquisition of novel molecular capabilities, an increasing amount of information from new model systems suggest that co-option and redirection of preexisting systems are the major source of innovation. We combine evidence from a wide range of organisms to obtain an integrated view of the origins and patterns of divergence in adaptive immunity. PMID:20651744

  14. 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.

  15. Adaptive Immune Regulation of Glial Homeostasis as an Immunization Strategy for Neurodegenerative Diseases

    PubMed Central

    Kosloski, Lisa M.; Ha, Duy M.; Stone, David K.; Hutter, Jessica A. L.; Pichler, Michael R.; Reynolds, Ashley D.; Gendelman, Howard E.; Mosley, R. Lee

    2010-01-01

    Neurodegenerative diseases, notably Alzheimer's and Parkinson's diseases, are amongst the most devastating disorders afflicting the elderly. Currently, no curative treatments or treatments that interdict disease progression exist. Over the past decade, immunization strategies have been proposed to combat disease progression. Such strategies induce humoral immune responses against misfolded protein aggregates to facilitate their clearance. Robust adaptive immunity against misfolded proteins, however, accelerates disease progression, precipitated by induced effector T cell responses that lead to encephalitis and neuronal death. Since then, mechanisms that attenuate such adaptive neurotoxic immune responses have been sought. We propose that shifting the balance between effector and regulatory T cell activity can attenuate neurotoxic inflammatory events. This review summarizes advances in immune regulation to achieve a homeostatic glial response for therapeutic gain. Promising new ways to optimize immunization schemes and measure their clinical efficacy are also discussed. PMID:20524958

  16. 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.

  17. Adaptive immune responses to Candida albicans infection

    PubMed Central

    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. PMID:25607781

  18. 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.

  19. 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.

  20. Immune Regulation by Pericytes: Modulating Innate and Adaptive Immunity

    PubMed Central

    Navarro, Rocío; Compte, Marta; Álvarez-Vallina, Luis; Sanz, Laura

    2016-01-01

    Pericytes (PC) are mural cells that surround endothelial cells in small blood vessels. PC have traditionally been credited with structural functions, being essential for vessel maturation and stabilization. However, an accumulating body of evidence suggests that PC also display immune properties. They can respond to a series of pro-inflammatory stimuli and are able to sense different types of danger due to their expression of functional pattern-recognition receptors, contributing to the onset of innate immune responses. In this context, PC not only secrete a variety of chemokines but also overexpress adhesion molecules such as ICAM-1 and VCAM-1 involved in the control of immune cell trafficking across vessel walls. In addition to their role in innate immunity, PC are involved in adaptive immunity. It has been reported that interaction with PC anergizes T cells, which is attributed, at least in part, to the expression of PD-L1. As components of the tumor microenvironment, PC can also modulate the antitumor immune response. However, their role is complex, and further studies will be required to better understand the crosstalk of PC with immune cells in order to consider them as potential therapeutic targets. In any case, PC will be looked at with new eyes by immunologists from now on. PMID:27867386

  1. Immunity to gastrointestinal nematodes: mechanisms and myths.

    PubMed

    Grencis, Richard K; Humphreys, Neil E; Bancroft, Allison J

    2014-07-01

    Immune responses to gastrointestinal nematodes have been studied extensively for over 80 years and intensively investigated over the last 30-40 years. The use of laboratory models has led to the discovery of new mechanisms of protective immunity and made major contributions to our fundamental understanding of both innate and adaptive responses. In addition to host protection, it is clear that immunoregulatory processes are common in infected individuals and resistance often operates alongside modulation of immunity. This review aims to discuss the recent discoveries in both host protection and immunoregulation against gastrointestinal nematodes, placing the data in context of the specific life cycles imposed by the different parasites studied and the future challenges of considering the mucosal/immune axis to encompass host, parasite, and microbiome in its widest sense.

  2. Immunity to gastrointestinal nematodes: mechanisms and myths

    PubMed Central

    Grencis, Richard K; Humphreys, Neil E; Bancroft, Allison J

    2014-01-01

    Immune responses to gastrointestinal nematodes have been studied extensively for over 80 years and intensively investigated over the last 30–40 years. The use of laboratory models has led to the discovery of new mechanisms of protective immunity and made major contributions to our fundamental understanding of both innate and adaptive responses. In addition to host protection, it is clear that immunoregulatory processes are common in infected individuals and resistance often operates alongside modulation of immunity. This review aims to discuss the recent discoveries in both host protection and immunoregulation against gastrointestinal nematodes, placing the data in context of the specific life cycles imposed by the different parasites studied and the future challenges of considering the mucosal/immune axis to encompass host, parasite, and microbiome in its widest sense. PMID:24942690

  3. The Influence of Innate and Adaptive Immune Responses on Atherosclerosis

    PubMed Central

    Witztum, Joseph L.; Lichtman, Andrew H.

    2014-01-01

    Both the chronic development of atherosclerotic lesions and the acute changes in lesion phenotype that lead to clinical cardiovascular events are significantly influenced by the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall. The rapid pace of discovery of mechanisms of immunologic recognition, effector functions, and regulation has significantly influenced the study of atherosclerosis, and our new knowledge is beginning to affect how we treat this ubiquitous disease. In this review, we discuss recent advances in our understanding of how innate and adaptive immunity contribute to atherosclerosis, as well as therapeutic opportunities that arise from this knowledge. PMID:23937439

  4. Host adaptive immunity alters gut microbiota.

    PubMed

    Zhang, Husen; Sparks, Joshua B; Karyala, Saikumar V; Settlage, Robert; Luo, Xin M

    2015-03-01

    It has long been recognized that the mammalian gut microbiota has a role in the development and activation of the host immune system. Much less is known on how host immunity regulates the gut microbiota. Here we investigated the role of adaptive immunity on the mouse distal gut microbial composition by sequencing 16 S rRNA genes from microbiota of immunodeficient Rag1(-/-) mice, versus wild-type mice, under the same housing environment. To detect possible interactions among immunological status, age and variability from anatomical sites, we analyzed samples from the cecum, colon, colonic mucus and feces before and after weaning. High-throughput sequencing showed that Firmicutes, Bacteroidetes and Verrucomicrobia dominated mouse gut bacterial communities. Rag1(-) mice had a distinct microbiota that was phylogenetically different from wild-type mice. In particular, the bacterium Akkermansia muciniphila was highly enriched in Rag1(-/-) mice compared with the wild type. This enrichment was suppressed when Rag1(-/-) mice received bone marrows from wild-type mice. The microbial community diversity increased with age, albeit the magnitude depended on Rag1 status. In addition, Rag1(-/-) mice had a higher gain in microbiota richness and evenness with increase in age compared with wild-type mice, possibly due to the lack of pressure from the adaptive immune system. Our results suggest that adaptive immunity has a pervasive role in regulating gut microbiota's composition and diversity.

  5. Osteopontin Bridging Innate and Adaptive Immunity in Autoimmune Diseases

    PubMed Central

    Raineri, Davide; Boggio, Elena; Favero, Francesco; Soluri, Maria Felicia

    2016-01-01

    Osteopontin (OPN) regulates the immune response at multiple levels. Physiologically, it regulates the host response to infections by driving T helper (Th) polarization and acting on both innate and adaptive immunity; pathologically, it contributes to the development of immune-mediated and inflammatory diseases. In some cases, the mechanisms of these effects have been described, but many aspects of the OPN function remain elusive. This is in part ascribable to the fact that OPN is a complex molecule with several posttranslational modifications and it may act as either an immobilized protein of the extracellular matrix or a soluble cytokine or an intracytoplasmic molecule by binding to a wide variety of molecules including crystals of calcium phosphate, several cell surface receptors, and intracytoplasmic molecules. This review describes the OPN structure, isoforms, and functions and its role in regulating the crosstalk between innate and adaptive immunity in autoimmune diseases. PMID:28097158

  6. Interferon regulatory factor 3 in adaptive immune responses.

    PubMed

    Ysebrant de Lendonck, Laure; Martinet, Valerie; Goriely, Stanislas

    2014-10-01

    Interferon regulatory factor (IRF) 3 plays a key role in innate responses against viruses. Indeed, activation of this transcription factor triggers the expression of type I interferons and downstream interferon-stimulated genes in infected cells. Recent evidences indicate that this pathway also modulates adaptive immune responses. This review focuses on the different mechanisms that are implicated in this process. We discuss the role of IRF3 within antigen-presenting cells and T lymphocytes in the polarization of the cellular immune response and its implication in the pathogenesis of immune disorders.

  7. Adaptive immune responses to Acanthamoeba cysts.

    PubMed

    McClellan, Kathy; Howard, Kevin; Mayhew, Elizabeth; Niederkorn, Jerry; Alizadeh, Hassan

    2002-09-01

    Acanthamoeba cysts are not eliminated from the corneas of human subjects or experimentally infected animals. The persistence of Acanthamoeba cysts in the cornea indicates that either the cysts escape immunological elimination or are not recognized by the host's immunological elements. The aim of this study was to determine the immunogenicity and antigenicity of the Acanthamoeba cyst. Mice were immunized intraperitoneally and serum anti-Acanthamoeba IgG was measured by ELISA. Lymphoproliferative assay and delayed type hypersensitivity (DTH) responses to Acanthamoeba castellanii cyst and trophozoite antigens were used to determine the cell mediated immune responses against Acanthamoeba cysts. A. castellanii cysts were both immunogenic and antigenic, producing anti-Acanthamoeba serum IgG, T lymphocyte proliferation, and delayed type hypersensitivity responses. These results indicate that Acanthamoeba cysts are recognized by the immune system. The persistence of the organism in the human cornea means that these adaptive immune responses fail to kill Acanthamoeba cysts.

  8. New insights into immune mechanisms of vitiligo.

    PubMed

    Boniface, Katia; Taïeb, Alain; Seneschal, Julien

    2016-02-01

    Vitiligo is the most common depigmenting disorder, affecting 0.5% of the population. This stigmatizing disease has a major social impact with high unmet needs, and no real curative intervention has been reported so far. Vitiligo is characterized by the development of white macules resulting from a loss of epidermal melanocytes, which can result from cell destruction through melanocyte-specific cytotoxic immune response and melanocyte detachment through a defective adhesion system. Multiple mechanisms have been suggested to be involved in melanocyte disappearance: genetic predisposition, environmental triggers, metabolic abnormalities, altered inflammatory and immune responses. The autoimmune and inflammatory theory is the leading hypothesis. Indeed, vitiligo is often associated with autoimmune diseases; genome-wide association studies and functional pathway analyses have shown that most vitiligo susceptibility loci encode components of the immune system; and immune cells are found in the perilesional margin of actively depigmenting skin of vitiligo patients. However, studies support melanocytes intrinsic abnormalities in vitiligo associated with increased melanocytes stress leading to the release of dangers signals important for the activation of the immune system. This review aimed to overview the link between cellular stress, melanocyte function, and the abnormal inflammatory immune response in vitiligo. The involvement of innate and adaptive immune cells in the pathomechanisms leading to melanocyte loss observed in vitiligo will be discussed.

  9. 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.

  10. Meeting the demand for innate and adaptive immunities during evolution.

    PubMed

    Du Pasquier, L

    2005-07-01

    An ideal immune system should provide each individual with rapid and efficient responses, a diverse repertoire of recognition and effector molecules and a certain flexibility to match the changing internal and external environment. It should be economic in cells and genes. Specific memory would be useful. It should not be autoreactive. These requirements, a mixture of innate and adaptive immunity features, are modulated in function of the dominant mode of selection for each species of metazoa during evolution (K or r). From sponges to man, a great diversity of receptors and effector mechanisms, some of them shared with plants, are articulated around conserved signalling cascades. Multiple attempts at combining innate and adaptive immunity somatic features can be observed as new somatic mechanisms provide individualized repertoires of receptors throughout metazoa, in agnathans, prochordates, echinoderms and mollusks. The adaptive immunity of vertebrates with lymphocytes and their specific receptors of the immunoglobulin superfamily, the major histocompatibility complex, developed from innate immunity evolutionary lines that can be traced back in earlier deuterostomes.

  11. Adaptive immunity in cancer immunology and therapeutics.

    PubMed

    Spurrell, Emma L; Lockley, Michelle

    2014-01-01

    The vast genetic alterations characteristic of tumours produce a number of tumour antigens that enable the immune system to differentiate tumour cells from normal cells. Counter to this, tumour cells have developed mechanisms by which to evade host immunity in their constant quest for growth and survival. Tumour-associated antigens (TAAs) are one of the fundamental triggers of the immune response. They are important because they activate, via major histocompatibility complex (MHC), the T cell response, an important line of defense against tumourigenesis. However, the persistence of tumours despite host immunity implies that tumour cells develop immune avoidance. An example of this is the up-regulation of inhibitory immune checkpoint proteins, by tumours, which induces a form of self-tolerance. The majority of monoclonal antibodies in clinical practice have been developed to target tumour-specific antigens. More recently there has been research in the down-regulation of immune checkpoint proteins as a way of increasing anti-tumour immunity.

  12. Protecting genome integrity during CRISPR immune adaptation.

    PubMed

    Wright, Addison V; Doudna, Jennifer A

    2016-10-01

    Bacterial CRISPR-Cas systems include genomic arrays of short repeats flanking foreign DNA sequences and provide adaptive immunity against viruses. Integration of foreign DNA must occur specifically to avoid damaging the genome or the CRISPR array, but surprisingly promiscuous activity occurs in vitro. Here we reconstituted full-site DNA integration and show that the Streptococcus pyogenes type II-A Cas1-Cas2 integrase maintains specificity in part through limitations on the second integration step. At non-CRISPR sites, integration stalls at the half-site intermediate, thereby enabling reaction reversal. S. pyogenes Cas1-Cas2 is highly specific for the leader-proximal repeat and recognizes the repeat's palindromic ends, thus fitting a model of independent recognition by distal Cas1 active sites. These findings suggest that DNA-insertion sites are less common than suggested by previous work, thereby preventing toxicity during CRISPR immune adaptation and maintaining host genome integrity.

  13. Adaptive immune cells temper initial innate responses

    PubMed Central

    Kim, Kwang Dong; Zhao, Jie; Auh, Sogyong; Yang, Xuanming; Du, Peishuang; Tang, Hong; Fu, Yang-Xin

    2008-01-01

    Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells1–4. Lymphocytedeficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1–deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25−Foxp3− or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses. PMID:17891146

  14. Adaptive immune cells temper initial innate responses.

    PubMed

    Kim, Kwang Dong; Zhao, Jie; Auh, Sogyong; Yang, Xuanming; Du, Peishuang; Tang, Hong; Fu, Yang-Xin

    2007-10-01

    Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells. Lymphocyte-deficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1-deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25-Foxp3- or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses.

  15. Immune mechanisms of HIV control

    PubMed Central

    Chakrabarti, Lisa A.; Simon, Viviana

    2010-01-01

    Summary HIV-1 can be contained by the immune system, as demonstrated by the existence of rare individuals who spontaneously control HIV-1 replication in the absence of antiretroviral therapy. Emerging evidence points to the importance of a very active cellular immune response in mediating HIV-1 control. The rapid induction of interferon-dependent HIV restriction factors, the presence of protective MHC class I alleles, and the development of a high avidity T-cell response may all cooperate in limiting HIV replication at an early stage. This review will focus on recent advances in understanding the immune mechanisms of HIV control, and on the lessons that may be drawn for the development of candidate HIV vaccines. PMID:20650621

  16. 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.

  17. The adaptive immune response in celiac disease.

    PubMed

    Qiao, Shuo-Wang; Iversen, Rasmus; Ráki, Melinda; Sollid, Ludvig M

    2012-07-01

    Compared to other human leukocyte antigen (HLA)-associated diseases such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, fundamental aspects of the pathogenesis in celiac disease are relatively well understood. This is mostly because the causative antigen in celiac disease-cereal gluten proteins-is known and the culprit HLA molecules are well defined. This has facilitated the dissection of the disease-relevant CD4+ T cells interacting with the disease-associated HLA molecules. In addition, celiac disease has distinct antibody responses to gluten and the autoantigen transglutaminase 2, which give strong handles to understand all sides of the adaptive immune response leading to disease. Here we review recent developments in the understanding of the role of T cells, B cells, and antigen-presenting cells in the pathogenic immune response of this instructive disorder.

  18. Immune evasion by cytomegalovirus--survival strategies of a highly adapted opportunist.

    PubMed

    Hengel, H; Brune, W; Koszinowski, U H

    1998-05-01

    Slowly replicating, species-specific and complex DNA viruses, such as cytomegaloviruses (CMVs), which code for > 200 antigenic proteins, should be easy prey to the host's immune system. Yet, CMVs are amazingly adapted opportunists that cope with multiple immune responses. Frequently, CMVs exploit immune mechanisms generated by the host. These strategies secure the persistence of CMVs and provide opportunities to spread to naive individuals.

  19. Integration of the immune system: a complex adaptive supersystem

    NASA Astrophysics Data System (ADS)

    Crisman, Mark V.

    2001-10-01

    Immunity to pathogenic organisms is a complex process involving interacting factors within the immune system including circulating cells, tissues and soluble chemical mediators. Both the efficiency and adaptive responses of the immune system in a dynamic, often hostile, environment are essential for maintaining our health and homeostasis. This paper will present a brief review of one of nature's most elegant, complex adaptive systems.

  20. Immune Mechanisms of Chronic Rhinosinusitis

    PubMed Central

    2016-01-01

    Chronic rhinosinusitis (CRS) is a common inflammatory disease that results in a significant decrease in patient quality of life and a large economic burden. However, the lack of population-based epidemiologic studies and robust model systems has made it difficult to fully elucidate the key inflammatory pathways that drive the chronic inflammatory responses observed in CRS. This review will highlight the wide variety of factors that likely contribute to CRS disease pathogenesis. Defects in the innate immune function of the airway epithelium, including decreases in barrier function, mucociliary clearance, and production of antimicrobial peptides, all likely play a role in the initial inflammatory response. Subsequent recruitment and activation of eosinophils, mast cells, and innate lymphoid cells (ILCs) further contributes to the chronic inflammatory response and directly activates adaptive immune cells, including T and B cells. However, development of new tools and model systems is still needed to further understand the chronicity of this inflammatory response and which specific factors are necessary or sufficient to drive CRS pathogenesis. Such studies will be critical for the development of improved therapeutic strategies aimed at treating this highly prevalent and costly disease. PMID:26677109

  1. 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.

  2. Evasion of Innate and Adaptive Immunity by Mycobacterium tuberculosis.

    PubMed

    Goldberg, Michael F; Saini, Neeraj K; Porcelli, Steven A

    2014-10-01

    Through thousands of years of reciprocal coevolution, Mycobacterium tuberculosis has become one of humanity's most successful pathogens, acquiring the ability to establish latent or progressive infection and persist even in the presence of a fully functioning immune system. The ability of M. tuberculosis to avoid immune-mediated clearance is likely to reflect a highly evolved and coordinated program of immune evasion strategies that interfere with both innate and adaptive immunity. These include the manipulation of their phagosomal environment within host macrophages, the selective avoidance or engagement of pattern recognition receptors, modulation of host cytokine production, and the manipulation of antigen presentation to prevent or alter the quality of T-cell responses. In this article we review an extensive array of published studies that have begun to unravel the sophisticated program of specific mechanisms that enable M. tuberculosis and other pathogenic mycobacteria to persist and replicate in the face of considerable immunological pressure from their hosts. Unraveling the mechanisms by which M. tuberculosis evades or modulates host immune function is likely to be of major importance for the development of more effective new vaccines and targeted immunotherapy against tuberculosis.

  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. Natural Killer Cells Can Inhibit the Transmission of Human Cytomegalovirus in Cell Culture by Using Mechanisms from Innate and Adaptive Immune Responses

    PubMed Central

    Wu, Zeguang; Sinzger, Christian; Reichel, Johanna Julia; Just, Marlies

    2014-01-01

    ABSTRACT Human cytomegalovirus (HCMV) transmission within the host is important for the pathogenesis of HCMV diseases. Natural killer (NK) cells are well known to provide a first line of host defense against virus infections. However, the role of NK cells in the control of HCMV transmission is still unknown. Here, we provide the first experimental evidence that NK cells can efficiently control HCMV transmission in different cell types. NK cells engage different mechanisms to control the HCMV transmission both via soluble factors and by cell contact. NK cell-produced interferon gamma (IFN-γ) suppresses HCMV production and induces resistance of bystander cells to HCMV infection. The UL16 viral gene contributes to an immune evasion from the NK cell-mediated control of HCMV transmission. Furthermore, the efficacy of the antibody-dependent NK cell-mediated control of HCMV transmission is dependent on a CD16-158V/F polymorphism. Our findings indicate that NK cells may have a clinical relevance in HCMV infection and highlight the need to consider potential therapeutic strategies based on the manipulation of NK cells. IMPORTANCE Human cytomegalovirus (HCMV) infects 40% to 100% of the human population worldwide. After primary infection, mainly in childhood, the virus establishes a lifelong persistence with possible reactivations. Most infections remain asymptomatic; however, HCMV represents a major health problem since it is the most frequent cause of infection-induced birth defects and is responsible for high morbidity and mortality in immunocompromised patients. The immune system normally controls the infection by antibodies and immune effector cells. One type of effector cells are the natural killer (NK) cells, which provide a rapid response to virus-infected cells. NK cells participate in viral clearance by inducing the death of infected cells. NK cells also secrete antiviral cytokines as a consequence of the interaction with an infected cell. In this study, we

  5. Immune mechanisms in hypertension and vascular injury.

    PubMed

    Schiffrin, Ernesto L

    2014-02-01

    Over the last 20 years it has become recognized that low-grade inflammation plays a role in cardiovascular disease. More recently, participation of the innate and the adaptive immune response in mechanisms that contribute to inflammation in cardiovascular disease has been reported in atherosclerosis and hypertension. Different subsets of lymphocytes and their cytokines are involved in vascular remodelling in hypertension, chronic kidney disease and heart disease. Effector T-cells include Th1 (interferon-γ-producing) and Th2 (interleukin-4 producing) lymphocytes, as well as Th17 (which produce interleukin-17) and T-suppressor lymphocytes such as T(reg)-cells (regulatory T-cells), which express the transcription factor Foxp3 (forkhead box P3) and participate respectively as pro- and anti-inflammatory cells. Pro-inflammatory T-lymphocytes participate in mechanisms of cardiovascular disease in part by mediating the effects of angiotensin II and mineralocorticoids. Involvement of immune mechanisms in cardiac, vascular and renal changes in hypertension has been demonstrated in many experimental models, an example being the Dahl-salt sensitive rat and the spontaneously hypertensive rat. How activation of immunity is triggered remains unknown, but neo-antigens could be generated by elevated blood pressure through damage-associated molecular pattern receptors or other mechanisms. Once activated, Th1 cells may contribute to blood pressure elevation by affecting the kidney, vascular remodelling of blood vessels directly via the effects of the cytokines produced or through their effects on perivascular fat. T(reg)-cells protect from blood pressure elevation by acting upon similar targets. Recent data suggests that participation of these mechanisms that have been demonstrated already in murine models also occurs in humans. These novel findings may open the way for new therapeutic approaches to improve outcomes in hypertension and cardiovascular disease in humans.

  6. The evolution of adaptive immunity in vertebrates.

    PubMed

    Hirano, Masayuki; Das, Sabyasachi; Guo, Peng; Cooper, Max D

    2011-01-01

    Approximately 500 million years ago, two types of recombinatorial adaptive immune systems (AISs) arose in vertebrates. The jawed vertebrates diversify their repertoire of immunoglobulin domain-based T and B cell antigen receptors mainly through the rearrangement of V(D)J gene segments and somatic hypermutation, but none of the fundamental AIS recognition elements in jawed vertebrates have been found in jawless vertebrates. Instead, the AIS of jawless vertebrates is based on variable lymphocyte receptors (VLRs) that are generated through recombinatorial usage of a large panel of highly diverse leucine-rich-repeat (LRR) sequences. Whereas the appearance of transposon-like, recombination-activating genes contributed uniquely to the origin of the AIS in jawed vertebrates, the use of activation-induced cytidine deaminase for receptor diversification is common to both the jawed and jawless vertebrates. Despite these differences in anticipatory receptor construction, the basic AIS design featuring two interactive T and B lymphocyte arms apparently evolved in an ancestor of jawed and jawless vertebrates within the context of preexisting innate immunity and has been maintained since as a consequence of powerful and enduring selection, most probably for pathogen defense purposes.

  7. Manipulation of Innate and Adaptive Immunity through Cancer Vaccines

    PubMed Central

    Mitchell, Duane A.

    2017-01-01

    Although cancer immunotherapy has shown significant promise in mediating efficacious responses, it remains encumbered by tumor heterogeneity, loss of tumor-specific antigen targets, and the regulatory milieu both regionally and systemically. Cross talk between the innate and adaptive immune response may be requisite to polarize sustained antigen specific immunity. Cancer vaccines can serve as an essential fulcrum in initiating innate immunity while molding and sustaining adaptive immunity. Although peptide vaccines have shown tepid responses in a therapeutic setting with poor correlates for immune activity, RNA vaccines activate innate immune responses and have shown promising effects in preclinical and clinical studies based on enhanced DC migration. While the mechanistic insights behind the interplay between innate and adaptive immunity may be unique to the immunotherapeutic being investigated, understanding this dynamic is important to coordinate the different arms of the immune response in a focused response against cancer antigens. PMID:28265580

  8. Chronic infection and the origin of adaptive immune system.

    PubMed

    Usharauli, David

    2010-08-01

    It has been speculated that the rise of the adaptive immune system in jawed vertebrates some 400 million years ago gave them a superior protection to detect and defend against pathogens that became more elusive and/or virulent to the host that had only innate immune system. First, this line of thought implies that adaptive immune system was a new, more sophisticated layer of host defense that operated independently of the innate immune system. Second, the natural consequence of this scenario would be that pathogens would have exercised so strong an evolutionary pressure that eventually no host could have afforded not to have an adaptive immune system. Neither of these arguments is supported by the facts. First, new experimental evidence has firmly established that operation of adaptive immune system is critically dependent on the ability of the innate immune system to detect invader-pathogens and second, the absolute majority of animal kingdom survives just fine with only an innate immune system. Thus, these data raise the dilemma: If innate immune system was sufficient to detect and protect against pathogens, why then did adaptive immune system develop in the first place? In contrast to the innate immune system, the adaptive immune system has one important advantage, precision. By precision I mean the ability of the defense system to detect and remove the target, for example, infected cells, without causing unwanted bystander damage of surrounding tissue. While the target precision per se is not important for short-term immune response, it becomes a critical factor when the immune response is long-lasting, as during chronic infection. In this paper I would like to propose new, "toxic index" hypothesis where I argue that the need to reduce the collateral damage to the tissue during chronic infection(s) was the evolutionary pressure that led to the development of the adaptive immune system.

  9. Adaptive immune response during hepatitis C virus infection.

    PubMed

    Larrubia, Juan Ramón; Moreno-Cubero, Elia; Lokhande, Megha Uttam; García-Garzón, Silvia; Lázaro, Alicia; Miquel, Joaquín; Perna, Cristian; Sanz-de-Villalobos, Eduardo

    2014-04-07

    Hepatitis C virus (HCV) infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control. Liver damage and disease progression during HCV infection are driven by both viral and host factors. Specifically, adaptive immune response carries out an essential task in controlling non-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery. HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion. To impair HCV-specific T cell reactivity, HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro- and anti-apoptotic proteins. In this review, the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

  10. Analysis of differential immune responses induced by innate and adaptive immunity following transplantation

    PubMed Central

    He, Hongzhen; Stone, James R; Perkins, David L

    2003-01-01

    The roles of innate and adaptive immunity in allograft rejection remain incompletely understood. Previous studies analysing lymphocyte deficient or syngeneic graft recipients have identified subsets of inflammatory chemokines and cytokines induced by antigen independent mechanisms. In the current study, we analysed a panel of 60 inflammatory parameters including serum cytokines, intragraft chemokines and cytokines, receptors, and cellular markers. Our results confirmed the up-regulation of a subset of markers by innate mechanisms and also identified a subset of parameters up-regulated only in the context of an adaptive response. Thus, we successfully differentiated markers of the innate and adaptive phases of rejection. Current paradigms emphasize that innate signals can promote a subsequent adaptive response. Interestingly, in our studies, expression of the markers induced by innate mechanisms was markedly amplified in the allogeneic, but not syngeneic or lymphocyte deficient, recipients. These results suggest that inflammatory mediators can have functional overlap between the innate and adaptive responses, and that the adaptive component of the rejection process amplifies the innate response by positive feedback regulation. PMID:12757613

  11. Did the molecules of adaptive immunity evolve from the innate immune system?

    PubMed

    Bartl, Simona; Baish, Meredith; Weissman, Irving L; Diaz, Marilyn

    2003-04-01

    The antigen receptors on cells of innate immune systems recognize broadly expressed markers on non-host cells while the receptors on lymphocytes of the adaptive immune system display a higher level of specificity. Adaptive immunity, with its exquisite specificity and immunological memory, has only been found in the jawed vertebrates, which also display innate immunity. Jawless fishes and invertebrates only have innate immunity. In the adaptive immune response, T and B-lymphocytes detect foreign agents or antigens using T cell receptors (TCR) or immunoglobulins (Ig), respectively. While Ig can bind free intact antigens, TCR only binds processed antigenic fragments that are presented on molecules encoded in the major histocompatibility complex (MHC). MHC molecules display variation through allelic polymorphism. A diverse repertoire of Ig and TCR molecules is generated by gene rearrangement and junctional diversity, processes carried out by the recombinase activating gene (RAG) products and terminal deoxynucleotidyl transferase (TdT). Thus, the molecules that define adaptive immunity are TCR, Ig, MHC molecules, RAG products and TdT. No direct predecessors of these molecules have been found in the jawless fishes or invertebrates. In contrast, the complement cascade can be activated by either adaptive or innate immune systems and contains examples of molecules that gradually evolved from non-immune functions to being part of the innate and then adaptive immune system. In this paper we examine the molecules of the adaptive immune system and speculate on the existence of direct predecessors that were part of innate immunity.

  12. Cellular immune mechanisms in myocarditis.

    PubMed

    Noutsias, M; Patil, V J; Maisch, B

    2012-12-01

    The introduction of immunohistological techniques enabled a substantially more reliable diagnosis of inflammatory cardiomyopathy (DCMi) in endomyocardial biopsies (EMB) compared to the histological Dallas criteria. Decisive progress has been made in the understanding of cellular immune mechanisms in DCMi using immunohistological techniques, which apart from the field of diagnosis refinement have had prognostic implications and an influence on the selection criteria of DCMi patients who will likely benefit from immunosuppressive treatment. Digital image analysis systems have been employed to standardize quantification of immunohistological EMB stainings. Quantification of T cell-related genes by a methodologically validated preamplified real-time RT-PCR revealed that the T cells are characterized by differential expression of Th1-, Treg-, and CTL-related markers, while no major role could be confirmed for Th17 cells. The reported virus-associated differential T cell receptor Vbeta dominance suggests an antiviral specificity of virus-induced T cell responses in human DCMi.

  13. Glatiramer Acetate in Treatment of Multiple Sclerosis: A Toolbox of Random Co-Polymers for Targeting Inflammatory Mechanisms of both the Innate and Adaptive Immune System?

    PubMed Central

    Jalilian, Babak; Einarsson, Halldór Bjarki; Vorup-Jensen, Thomas

    2012-01-01

    Multiple sclerosis is a disease of the central nervous system, resulting in the demyelination of neurons, causing mild to severe symptoms. Several anti-inflammatory treatments now play a significant role in ameliorating the disease. Glatiramer acetate (GA) is a formulation of random polypeptide copolymers for the treatment of relapsing-remitting MS by limiting the frequency of attacks. While evidence suggests the influence of GA on inflammatory responses, the targeted molecular mechanisms remain poorly understood. Here, we review the multiple pharmacological modes-of-actions of glatiramer acetate in treatment of multiple sclerosis. We discuss in particular a newly discovered interaction between the leukocyte-expressed integrin αMβ2 (also called Mac-1, complement receptor 3, or CD11b/CD18) and perspectives on the GA co-polymers as an influence on the function of the innate immune system. PMID:23203082

  14. Long non-coding RNAs in innate and adaptive immunity

    PubMed Central

    Aune, Thomas M.; Spurlock, Charles F.

    2015-01-01

    Long noncoding RNAs (lncRNAs) represent a newly discovered class of regulatory molecules that impact a variety of biological processes in cells and organ systems. In humans, it is estimated that there may be more than twice as many lncRNA genes than protein-coding genes. However, only a handful of lncRNAs have been analyzed in detail. In this review, we describe expression and functions of lncRNAs that have been demonstrated to impact innate and adaptive immunity. These emerging paradigms illustrate remarkably diverse mechanisms that lncRNAs utilize to impact the transcriptional programs of immune cells required to fight against pathogens and maintain normal health and homeostasis. PMID:26166759

  15. Unique Features of Fish Immune Repertoires: Particularities of Adaptive Immunity Within the Largest Group of Vertebrates.

    PubMed

    Magadan, Susana; Sunyer, Oriol J; Boudinot, Pierre

    2015-01-01

    Fishes (i.e., teleost fishes) are the largest group of vertebrates. Although their immune system is based on the fundamental receptors, pathways, and cell types found in all groups of vertebrates, fishes show a diversity of particular features that challenge some classical concepts of immunology. In this chapter, we discuss the particularities of fish immune repertoires from a comparative perspective. We examine how allelic exclusion can be achieved when multiple Ig loci are present, how isotypic diversity and functional specificity impact clonal complexity, how loss of the MHC class II molecules affects the cooperation between T and B cells, and how deep sequencing technologies bring new insights about somatic hypermutation in the absence of germinal centers. The unique coexistence of two distinct B-cell lineages respectively specialized in systemic and mucosal responses is also discussed. Finally, we try to show that the diverse adaptations of immune repertoires in teleosts can help in understanding how somatic adaptive mechanisms of immunity evolved in parallel in different lineages across vertebrates.

  16. Unique Features of Fish Immune Repertoires: Particularities of Adaptive Immunity Within the Largest Group of Vertebrates

    PubMed Central

    Sunyer, Oriol J.

    2016-01-01

    Fishes (i.e., teleost fishes) are the largest group of vertebrates. Although their immune system is based on the fundamental receptors, pathways, and cell types found in all groups of vertebrates, fishes show a diversity of particular features that challenge some classical concepts of immunology. In this chapter, we discuss the particularities of fish immune repertoires from a comparative perspective. We examine how allelic exclusion can be achieved when multiple Ig loci are present, how isotypic diversity and functional specificity impact clonal complexity, how loss of the MHC class II molecules affects the cooperation between T and B cells, and how deep sequencing technologies bring new insights about somatic hypermutation in the absence of germinal centers. The unique coexistence of two distinct B-cell lineages respectively specialized in systemic and mucosal responses is also discussed. Finally, we try to show that the diverse adaptations of immune repertoires in teleosts can help in understanding how somatic adaptive mechanisms of immunity evolved in parallel in different lineages across vertebrates. PMID:26537384

  17. Diversity Against Adversity: How Adaptive Immune System Evolves Potent Antibodies

    NASA Astrophysics Data System (ADS)

    Heo, Muyoung; Zeldovich, Konstantin B.; Shakhnovich, Eugene I.

    2011-07-01

    Adaptive immunity is an amazing mechanism, whereby new protein functions—affinity of antibodies (Immunoglobulins) to new antigens—evolve through mutation and selection in a matter of a few days. Despite numerous experimental studies, the fundamental physical principles underlying immune response are still poorly understood. In considerable departure from past approaches, here, we propose a microscopic multiscale model of adaptive immune response, which consists of three essential players: The host cells, viruses, and B-cells in Germinal Centers (GC). Each moiety carries a genome, which encodes proteins whose stability and interactions are determined from their sequences using laws of Statistical Mechanics, providing an exact relationship between genomic sequences and strength of interactions between pathogens and antibodies and antibodies and host proteins (autoimmunity). We find that evolution of potent antibodies (the process known as Affinity Maturation (AM)) is a delicate balancing act, which has to reconcile the conflicting requirements of protein stability, lack of autoimmunity, and high affinity of antibodies to incoming antigens. This becomes possible only when antibody producing B cells elevate their mutation rates (process known as Somatic Hypermutation (SHM)) to fall into a certain range—not too low to find potency increasing mutations but not too high to destroy stable Immunoglobulins and/or already achieved affinity. Potent antibodies develop through clonal expansion of initial B cells expressing marginally potent antibodies followed by their subsequent affinity maturation through mutation and selection. As a result, in each GC the population of mature potent Immunoglobulins is monoclonal being ancestors of a single cell from initial (germline) pool. We developed a simple analytical theory, which provides further rationale to our findings. The model and theory reveal the molecular factors that determine the efficiency of affinity maturation

  18. Linear ubiquitination signals in adaptive immune responses.

    PubMed

    Ikeda, Fumiyo

    2015-07-01

    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-κB (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.

  19. Immune mechanism: a 'double-edged sword'.

    PubMed

    Musa, Mustaffa

    2013-05-01

    Immunology has now developed into an independent discipline in medicine which covers not only germ infection which is related to immunity solely but also covers a lot of non-infectious diseases such as autoimmune disease, allergies, and others. Therefore, "The Immune Mechanism: "A Double-Edged Sword" means that the immune mechanism (consisted of antibody mediated mechanism and T cell mediated mechanism), just like one edge playing the role of giving benefit (immunity) as it destroys the agent of infection, and another one can be detrimental as it will cause tissue/cell damages and then give rise to immune diseases (immunopathology). Now, the prevalence of these immune diseases is on the rise and has become a new challenge to our country towards developed country in 2020. Therefore, we have to make ample preparation (laboratory facilities/services, main power, and research) from now on in order to face the problems and challenges.

  20. The CRISPR-Cas immune system: biology, mechanisms and applications.

    PubMed

    Rath, Devashish; Amlinger, Lina; Rath, Archana; Lundgren, Magnus

    2015-10-01

    Viruses are a common threat to cellular life, not the least to bacteria and archaea who constitute the majority of life on Earth. Consequently, a variety of mechanisms to resist virus infection has evolved. A recent discovery is the adaptive immune system in prokaryotes, a type of system previously thought to be present only in vertebrates. The system, called CRISPR-Cas, provide sequence-specific adaptive immunity and fundamentally affect our understanding of virus-host interaction. CRISPR-based immunity acts by integrating short virus sequences in the cell's CRISPR locus, allowing the cell to remember, recognize and clear infections. There has been rapid advancement in our understanding of this immune system and its applications, but there are many aspects that await elucidation making the field an exciting area of research. This review provides an overview of the field and highlights unresolved issues.

  1. Innate immune mechanisms in vitiligo: danger from within.

    PubMed

    Richmond, Jillian M; Frisoli, Michael L; Harris, John E

    2013-12-01

    Vitiligo is an autoimmune disease of the skin in which melanocytes are destroyed by antigen-specific T cells, resulting in patchy depigmentation. Although adaptive immunity plays a clear role in disease progression, initiating factors are largely unknown. Many studies report that cellular stress pathways are dysregulated in melanocytes from vitiligo patients, suggesting that melanocyte-intrinsic defects participate in disease pathogenesis. Recent studies reveal that melanocyte stress generates damage-associated molecular patterns that activate innate immunity, thus connecting stress to organ-specific inflammation. Genetic studies in vitiligo support a role for stress, innate immunity, and adaptive mechanisms. Here, we discuss advances in the field that highlight how cellular stress, endogenous danger signals, and innate immune activation promote the onset of vitiligo.

  2. PD-1 blockade induces responses by inhibiting adaptive immune resistance

    PubMed Central

    Tumeh, Paul C.; Harview, Christina L.; Yearley, Jennifer H.; Shintaku, I. Peter; Taylor, Emma J. M.; Robert, Lidia; Chmielowski, Bartosz; Spasic, Marko; Henry, Gina; Ciobanu, Voicu; West, Alisha N.; Carmona, Manuel; Kivork, Christine; Seja, Elizabeth; Cherry, Grace; Gutierrez, Antonio; Grogan, Tristan R.; Mateus, Christine; Tomasic, Gorana; Glaspy, John A.; Emerson, Ryan O.; Robins, Harlan; Pierce, Robert H.; Elashoff, David A.; Robert, Caroline; Ribas, Antoni

    2014-01-01

    Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types.1–5 One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8 T-cells (termed adaptive immune resistance).6,7 Here we show that pre-existing CD8 T-cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analyzed samples from 46 patients with metastatic melanoma obtained before and during anti-PD1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next generation sequencing for T-cell receptors (TCR). In serially sampled tumours, responding patients showed proliferation of intratumoural CD8+ T-cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8, PD1, and PD-L1 expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression following therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1 mediated adaptive immune resistance. PMID:25428505

  3. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression

    PubMed Central

    DeNardo, David G; Coussens, Lisa M

    2007-01-01

    Recent insights into the molecular and cellular mechanisms underlying cancer development have revealed that immune cells functionally regulate epithelial cancer development and progression. Moreover, accumulated clinical and experimental data indicate that the outcome of an immune response toward an evolving breast neoplasm is largely determined by the type of immune response elicited. Acute tumor-directed immune responses involving cytolytic T lymphocytes appear to protect against tumor development, whereas immune responses involving chronic activation of humoral immunity, infiltration by Th2 cells, and protumor-polarized innate inflammatory cells result in the promotion of tumor development and disease progression. Herein we review this body of literature and summarize important new findings revealing the paradoxical role of innate and adaptive leukocytes as regulators of breast carcinogenesis. PMID:17705880

  4. Immune escape mechanisms in colorectal cancer pathogenesis and liver metastasis.

    PubMed

    Pancione, Massimo; Giordano, Guido; Remo, Andrea; Febbraro, Antonio; Sabatino, Lina; Manfrin, Erminia; Ceccarelli, Michele; Colantuoni, Vittorio

    2014-01-01

    Over the past decade, growing evidence indicates that the tumor microenvironment (TME) contributes with genomic/epigenomic aberrations of malignant cells to enhance cancer cells survival, invasion, and dissemination. Many factors, produced or de novo synthesized by immune, stromal, or malignant cells, acting in a paracrine and autocrine fashion, remodel TME and the adaptive immune response culminating in metastasis. Taking into account the recent accomplishments in the field of immune oncology and using metastatic colorectal cancer (mCRC) as a model, we propose that the evasion of the immune surveillance and metastatic spread can be achieved through a number of mechanisms that include (a) intrinsic plasticity and adaptability of immune and malignant cells to paracrine and autocrine stimuli or genotoxic stresses; (b) alteration of positional schemes of myeloid-lineage cells, produced by factors controlling the balance between tumour-suppressing and tumour-promoting activities; (c) acquisition by cancer cells of aberrant immune-phenotypic traits (NT5E/CD73, CD68, and CD163) that enhance the interactions among TME components through the production of immune-suppressive mediators. These properties may represent the driving force of metastatic progression and thus clinically exploitable for cancer prevention and therapy. In this review we summarize results and suggest new hypotheses that favour the growing impact of tumor-infiltrating immune cells on tumour progression, metastasis, and therapy resistance.

  5. Pathogenesis of innate immunity and adaptive immunity in the mouse model of experimental autoimmune uveitis.

    PubMed

    Bi, Hong-Sheng; Liu, Zheng-Feng; Cui, Yan

    2015-05-01

    Experimental autoimmune uveitis, a well-established model for human uveitis, is similar to human uveitis in many pathological features. Studies concerning the mechanisms of experimental autoimmune uveitis would cast a light on the pathogenesis of human uveitis as well as the search for more effective therapeutic agents. The cellular components of innate immunity include natural killer cells, gamma delta T lymphocytes, antigen-presenting dendritic cells, phagocytic macrophages, and granulocytes. It is believed that T cells are central in the generation of human uveitis. It has already become clear that CD4(+) effecter cells that predominantly produce interleukin-17 (the so-called Th17 cells) may play an important role in uveitis. In addition, the occurrence and recurrence of uveitis depends on a complex interplay between the elements of innate and adaptive immunity.

  6. Norovirus Mechanisms of Immune Antagonism

    PubMed Central

    Roth, Alexa N.; Karst, Stephanie M.

    2015-01-01

    Noroviruses are a leading cause of gastroenteritis outbreaks globally. Several lines of evidence indicate that noroviruses can antagonize or evade host immune responses, including the absence of long-lasting immunity elicited during a primary norovirus exposure and the ability of noroviruses to establish prolonged infections that are associated with protracted viral shedding. Specific norovirus proteins possessing immune antagonist activity have been described in recent years although mechanistic insight in most cases is limited. In this review, we discuss these emerging strategies used by noroviruses to subvert the immune response, including the actions of two nonstructural proteins (p48 and p22) to impair cellular protein trafficking and secretory pathways; the ability of the VF1 protein to inhibit cytokine induction; and the ability of the minor structural protein VP2 to regulate antigen presentation. We also discuss the current state of the understanding of host and viral factors regulating the establishment of persistent norovirus infections along the gastrointestinal tract. A more detailed understanding of immune antagonism by pathogenic viruses will inform prevention and treatment of disease. PMID:26673810

  7. Macrophages Subvert Adaptive Immunity to Urinary Tract Infection

    PubMed Central

    Mora-Bau, Gabriela; Platt, Andrew M.; van Rooijen, Nico; Randolph, Gwendalyn J.; Albert, Matthew L.; Ingersoll, Molly A.

    2015-01-01

    Urinary tract infection (UTI) is one of the most common bacterial infections with frequent recurrence being a major medical challenge. Development of effective therapies has been impeded by the lack of knowledge of events leading to adaptive immunity. Here, we establish conclusive evidence that an adaptive immune response is generated during UTI, yet this response does not establish sterilizing immunity. To investigate the underlying deficiency, we delineated the naïve bladder immune cell compartment, identifying resident macrophages as the most populous immune cell. To evaluate their impact on the establishment of adaptive immune responses following infection, we measured bacterial clearance in mice depleted of either circulating monocytes, which give rise to macrophages, or bladder resident macrophages. Surprisingly, mice depleted of resident macrophages, prior to primary infection, exhibited a nearly 2-log reduction in bacterial burden following secondary challenge compared to untreated animals. This increased bacterial clearance, in the context of a challenge infection, was dependent on lymphocytes. Macrophages were the predominant antigen presenting cell to acquire bacteria post-infection and in their absence, bacterial uptake by dendritic cells was increased almost 2-fold. These data suggest that bacterial uptake by tissue macrophages impedes development of adaptive immune responses during UTI, revealing a novel target for enhancing host responses to bacterial infection of the bladder. PMID:26182347

  8. Macrophages Subvert Adaptive Immunity to Urinary Tract Infection.

    PubMed

    Mora-Bau, Gabriela; Platt, Andrew M; van Rooijen, Nico; Randolph, Gwendalyn J; Albert, Matthew L; Ingersoll, Molly A

    2015-07-01

    Urinary tract infection (UTI) is one of the most common bacterial infections with frequent recurrence being a major medical challenge. Development of effective therapies has been impeded by the lack of knowledge of events leading to adaptive immunity. Here, we establish conclusive evidence that an adaptive immune response is generated during UTI, yet this response does not establish sterilizing immunity. To investigate the underlying deficiency, we delineated the naïve bladder immune cell compartment, identifying resident macrophages as the most populous immune cell. To evaluate their impact on the establishment of adaptive immune responses following infection, we measured bacterial clearance in mice depleted of either circulating monocytes, which give rise to macrophages, or bladder resident macrophages. Surprisingly, mice depleted of resident macrophages, prior to primary infection, exhibited a nearly 2-log reduction in bacterial burden following secondary challenge compared to untreated animals. This increased bacterial clearance, in the context of a challenge infection, was dependent on lymphocytes. Macrophages were the predominant antigen presenting cell to acquire bacteria post-infection and in their absence, bacterial uptake by dendritic cells was increased almost 2-fold. These data suggest that bacterial uptake by tissue macrophages impedes development of adaptive immune responses during UTI, revealing a novel target for enhancing host responses to bacterial infection of the bladder.

  9. Evolution of innate and adaptive immune systems in jawless vertebrates.

    PubMed

    Kasamatsu, Jun

    2013-01-01

    Because jawless vertebrates are the most primitive vertebrates, they have been studied to gain understanding of the evolutionary processes that gave rise to the innate and adaptive immune systems in vertebrates. Jawless vertebrates have developed lymphocyte-like cells that morphologically resemble the T and B cells of jawed vertebrates, but they express variable lymphocyte receptors (VLRs) instead of the T and B cell receptors that specifically recognize antigens in jawed vertebrates. These VLRs act as antigen receptors, diversity being generated in their antigen-binding sites by assembly of highly diverse leucine-rich repeat modules. Therefore, jawless vertebrates have developed adaptive immune systems based on the VLRs. Although pattern recognition receptors, including Toll-like receptors (TLRs) and Rig-like receptors (RLRs), and their adaptor genes are conserved in jawless vertebrates, some transcription factor and inflammatory cytokine genes in the TLR and RLR pathways are not present. However, like jawed vertebrates, the initiation of adaptive immune responses in jawless vertebrates appears to require prior activation of the innate immune system. These observations imply that the innate immune systems of jawless vertebrates have a unique molecular basis that is distinct from that of jawed vertebrates. Altogether, although the molecular details of the innate and adaptive immune systems differ between jawless and jawed vertebrates, jawless vertebrates have developed versions of these immune systems that are similar to those of jawed vertebrates.

  10. CD98 at the crossroads of adaptive immunity and cancer.

    PubMed

    Cantor, Joseph M; Ginsberg, Mark H

    2012-03-15

    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.

  11. Let’s Tie the Knot: Marriage of Complement and Adaptive Immunity in Pathogen Evasion, for Better or Worse

    PubMed Central

    Bennett, Kaila M.; Rooijakkers, Suzan H. M.; Gorham, Ronald D.

    2017-01-01

    The complement system is typically regarded as an effector arm of innate immunity, leading to recognition and killing of microbial invaders in body fluids. Consequently, pathogens have engaged in an arms race, evolving molecules that can interfere with proper complement responses. However, complement is no longer viewed as an isolated system, and links with other immune mechanisms are continually being discovered. Complement forms an important bridge between innate and adaptive immunity. While its roles in innate immunity are well-documented, its function in adaptive immunity is less characterized. Therefore, it is no surprise that the field of pathogenic complement evasion has focused on blockade of innate effector functions, while potential inhibition of adaptive immune responses (via complement) has been overlooked to a certain extent. In this review, we highlight past and recent developments on the involvement of complement in the adaptive immune response. We discuss the mechanisms by which complement aids in lymphocyte stimulation and regulation, as well as in antigen presentation. In addition, we discuss microbial complement evasion strategies, and highlight specific examples in the context of adaptive immune responses. These emerging ties between complement and adaptive immunity provide a catalyst for future discovery in not only the field of adaptive immune evasion but in elucidating new roles of complement. PMID:28197139

  12. Let's Tie the Knot: Marriage of Complement and Adaptive Immunity in Pathogen Evasion, for Better or Worse.

    PubMed

    Bennett, Kaila M; Rooijakkers, Suzan H M; Gorham, Ronald D

    2017-01-01

    The complement system is typically regarded as an effector arm of innate immunity, leading to recognition and killing of microbial invaders in body fluids. Consequently, pathogens have engaged in an arms race, evolving molecules that can interfere with proper complement responses. However, complement is no longer viewed as an isolated system, and links with other immune mechanisms are continually being discovered. Complement forms an important bridge between innate and adaptive immunity. While its roles in innate immunity are well-documented, its function in adaptive immunity is less characterized. Therefore, it is no surprise that the field of pathogenic complement evasion has focused on blockade of innate effector functions, while potential inhibition of adaptive immune responses (via complement) has been overlooked to a certain extent. In this review, we highlight past and recent developments on the involvement of complement in the adaptive immune response. We discuss the mechanisms by which complement aids in lymphocyte stimulation and regulation, as well as in antigen presentation. In addition, we discuss microbial complement evasion strategies, and highlight specific examples in the context of adaptive immune responses. These emerging ties between complement and adaptive immunity provide a catalyst for future discovery in not only the field of adaptive immune evasion but in elucidating new roles of complement.

  13. Regulation of the adaptive immune system by innate lymphoid cells

    PubMed Central

    Hepworth, Matthew R.; Sonnenberg, Gregory F.

    2014-01-01

    Innate lymphoid cells (ILCs) are a group of lymphocytes that promote rapid cytokine-dependent innate immunity, inflammation and tissue repair. In addition, a growing body of evidence suggests ILCs can influence adaptive immune cell responses. During fetal development a subset of ILCs orchestrate the generation and maturation of secondary lymphoid tissues. Following birth, ILCs continue to modulate adaptive immune cell responses indirectly through interactions with stromal cells in lymphoid tissues and epithelial cells at barrier surfaces. In this review we summarize the current understanding of how ILCs modulate the magnitude and quality of adaptive immune cell responses, and in particular focus on recent evidence suggesting that ILCs can also directly regulate CD4+ T cells. Further, we discuss the implications that these pathways may have on human health and disease. PMID:24594491

  14. Ebola Virus Altered Innate and Adaptive Immune Response Signalling Pathways: Implications for Novel Therapeutic Approaches.

    PubMed

    Kumar, Anoop

    2016-01-01

    Ebola virus (EBOV) arise attention for their impressive lethality by the poor immune response and high inflammatory reaction in the patients. It causes a severe hemorrhagic fever with case fatality rates of up to 90%. The mechanism underlying this lethal outcome is poorly understood. In 2014, a major outbreak of Ebola virus spread amongst several African countries, including Leone, Sierra, and Guinea. Although infections only occur frequently in Central Africa, but the virus has the potential to spread globally. Presently, there is no vaccine or treatment is available to counteract Ebola virus infections due to poor understanding of its interaction with the immune system. Accumulating evidence indicates that the virus actively alters both innate and adaptive immune responses and triggers harmful inflammatory responses. In the literature, some reports have shown that alteration of immune signaling pathways could be due to the ability of EBOV to interfere with dendritic cells (DCs), which link innate and adaptive immune responses. On the other hand, some reports have demonstrated that EBOV, VP35 proteins act as interferon antagonists. So, how the Ebola virus altered the innate and adaptive immune response signaling pathways is still an open question for the researcher to be explored. Thus, in this review, I try to summarize the mechanisms of the alteration of innate and adaptive immune response signaling pathways by Ebola virus which will be helpful for designing effective drugs or vaccines against this lethal infection. Further, potential targets, current treatment and novel therapeutic approaches have also been discussed.

  15. Mechanism of immune evasion in breast cancer

    PubMed Central

    Wang, Mozhi; Zhang, Changwang; Song, Yongxi; Wang, Zhenning; Wang, Yaojia; Luo, Fang; Xu, Yujie; Zhao, Yi; Wu, Zhonghua; Xu, Yingying

    2017-01-01

    Breast cancer (BC) is the most common malignant tumor among women, with high morbidity and mortality. Its onset, development, metastasis, and prognosis vary among individuals due to the interactions between tumors and host immunity. Many diverse mechanisms have been associated with BC, with immune evasion being the most widely studied to date. Tumor cells can escape from the body’s immune response, which targets abnormal components and foreign bodies, using different approaches including modification of surface antigens and modulation of the surrounding environment. In this review, we summarize the mechanisms and factors that impact the immunoediting process and analyze their functions in detail. PMID:28352189

  16. Immune and stress responses in oysters with insights on adaptation.

    PubMed

    Guo, Ximing; He, Yan; Zhang, Linlin; Lelong, Christophe; Jouaux, Aude

    2015-09-01

    Oysters are representative bivalve molluscs that are widely distributed in world oceans. As successful colonizers of estuaries and intertidal zones, oysters are remarkably resilient against harsh environmental conditions including wide fluctuations in temperature and salinity as well as prolonged air exposure. Oysters have no adaptive immunity but can thrive in microbe-rich estuaries as filter-feeders. These unique adaptations make oysters interesting models to study the evolution of host-defense systems. Recent advances in genomic studies including sequencing of the oyster genome have provided insights into oyster's immune and stress responses underlying their amazing resilience. Studies show that the oyster genomes are highly polymorphic and complex, which may be key to their resilience. The oyster genome has a large gene repertoire that is enriched for immune and stress response genes. Thousands of genes are involved in oyster's immune and stress responses, through complex interactions, with many gene families expanded showing high sequence, structural and functional diversity. The high diversity of immune receptors and effectors may provide oysters with enhanced specificity in immune recognition and response to cope with diverse pathogens in the absence of adaptive immunity. Some members of expanded immune gene families have diverged to function at different temperatures and salinities or assumed new roles in abiotic stress response. Most canonical innate immunity pathways are conserved in oysters and supported by a large number of diverse and often novel genes. The great diversity in immune and stress response genes exhibited by expanded gene families as well as high sequence and structural polymorphisms may be central to oyster's adaptation to highly stressful and widely changing environments.

  17. Zinc in innate and adaptive tumor immunity

    PubMed Central

    2010-01-01

    Zinc is important. It is the second most abundant trace metal with 2-4 grams in humans. It is an essential trace element, critical for cell growth, development and differentiation, DNA synthesis, RNA transcription, cell division, and cell activation. Zinc deficiency has adverse consequences during embryogenesis and early childhood development, particularly on immune functioning. It is essential in members of all enzyme classes, including over 300 signaling molecules and transcription factors. Free zinc in immune and tumor cells is regulated by 14 distinct zinc importers (ZIP) and transporters (ZNT1-8). Zinc depletion induces cell death via apoptosis (or necrosis if apoptotic pathways are blocked) while sufficient zinc levels allows maintenance of autophagy. Cancer cells have upregulated zinc importers, and frequently increased zinc levels, which allow them to survive. Based on this novel synthesis, approaches which locally regulate zinc levels to promote survival of immune cells and/or induce tumor apoptosis are in order. PMID:21087493

  18. The immune system and its modulation mechanism in scallop.

    PubMed

    Song, Linsheng; Wang, Lingling; Zhang, Huan; Wang, Mengqiang

    2015-09-01

    Scallops are a cosmopolitan family of bivalves, and some of them are highly prized as dominant aquaculture species. In the past decades, there have been increasing studies on the basic biology and immunology of scallops, and this review summarizes the research progresses of immune system and its modulation mechanism in scallop. As invertebrate, scallops lack adaptive immunity and they have evolved an array of sophisticated strategies to recognize and eliminate various invaders by employing a set of molecules and cells. It is evident that basic immune reactions such as immune recognition, signal transduction, and effector synthesis involved in immune response are accomplished in a variety of ways. They rely upon an extensive repertoire of phagocytosis, apoptosis and encapsulation of the circulating hemocytes for eliminating invasive pathogens, as well as the production of immune effectors that are active against a large range of pathogens or sensitive for the environmental stress. Furthermore, the molecular constitutions, metabolic pathways and immunomodulation mechanisms of the primitive catecholaminergic, cholinergic, enkephalinergic system and NO system in scallop are also discussed, which can be taken as an entrance to better understand the origin and evolution of the neuroendocrine-immune regulatory network in lower invertebrates.

  19. The Host Immune Response to Streptococcus pneumoniae: Bridging Innate and Adaptive Immunity

    DTIC Science & Technology

    2006-07-06

    caused by penicillin -resistant Streptococcus pneumoniae in rabbits. Antimicrob. Agents Chemother. 46: 1760- 1765. Takeuchi, O., Hoshino, K., and...2006 2. REPORT TYPE 3. DATES COVERED 00-00-2006 to 00-00-2006 4. TITLE AND SUBTITLE The host immune response to Streptococcus pneumoniae ...host immune response to Streptococcus pneumoniae : bridging innate and adaptive immunity Katherine Shi-Hui Lee Thesis directed by: Clifford M

  20. Cancer immunoediting by the innate immune system in the absence of adaptive immunity.

    PubMed

    O'Sullivan, Timothy; Saddawi-Konefka, Robert; Vermi, William; Koebel, Catherine M; Arthur, Cora; White, J Michael; Uppaluri, Ravi; Andrews, Daniel M; Ngiow, Shin Foong; Teng, Michele W L; Smyth, Mark J; Schreiber, Robert D; Bui, Jack D

    2012-09-24

    Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2(-/-), and RAG2(-/-)x γc(-/-) mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2(-/-)x γc(-/-) mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting.

  1. Readapting the adaptive immune response - therapeutic strategies for atherosclerosis.

    PubMed

    Sage, Andrew P; Mallat, Ziad

    2017-01-04

    Cardiovascular diseases remain a major global health issue, with the development of atherosclerosis as a major underlying cause. Our treatment of cardiovascular disease has improved greatly over the past three decades, but much remains to be done reduce disease burden. Current priorities include reducing atherosclerosis advancement to clinically significant stages and preventing plaque rupture or erosion. Inflammation and involvement of the adaptive immune system influences all these aspects and therefore is one focus for future therapeutic development. The atherosclerotic vascular wall is now recognized to be invaded from both sides (arterial lumen and adventitia), for better or worse, by the adaptive immune system. Atherosclerosis is also affected at several stages by adaptive immune responses, overall providing many opportunities to target these responses and to reduce disease progression. Protective influences that may be defective in diseased individuals include humoral responses to modified LDL and regulatory T cell responses. There are many strategies in development to boost these pathways in humans, including vaccine-based therapies. The effects of various existing adaptive immune targeting therapies, such as blocking critical co-stimulatory pathways or B cell depletion, on cardiovascular disease are beginning to emerge with important consequences for both autoimmune disease patients and the potential for wider use of such therapies. Entering the translation phase for adaptive immune targeting therapies is an exciting and promising prospect.

  2. Evasion of innate and adaptive immune responses by influenza A virus.

    PubMed

    Schmolke, Mirco; García-Sastre, Adolfo

    2010-07-01

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

  3. [Local immune tolerance mechanisms in kidney cancer].

    PubMed

    Patard, Jean-Jacques; Bouet, Françoise; Rioux-Leclercq, Nathalie; Lobel, Bernard; Catros-Quemener, Véronique; Guillé, François

    2002-04-01

    Many arguments suggest that renal tumours are immunogenic. However, the immune cells present around or within the tumour are unable to induce tumour rejection and the results of immunotherapy in metastatic renal cancer remain disappointing regardless of the protocols used. The objective of this study was to review the main mechanisms by which a renal tumour can escape immune destruction. These mechanisms can concern: tumour antigens, antigen-presenting molecules on the cell surface or defects of the cell machinery leading to the preparation of these molecules. Defects may also concern intercellular communications, especially adhesion and co-stimulation molecules. The immune cells present may also be defective, presenting qualitative or quantitative deficits, abnormalities of the T receptor, defect of cytokine production and these defects may concern both effector cells and antigen-presenting cells. The capacity of tumour cells to release anergic substances, i.e. substances which paralyze the immune system, also constitutes another very powerful immunosuppressive mechanism. These substances are cytokines, especially TGF-b. This anergy can also be mediated by intercellular contacts between tumour cells and lymphocytes, especially via the Fas system. It is important to study these mechanisms for several reasons: 1/Understanding of anergy mechanisms in order to discover new therapeutic targets or to short-circuit these mechanisms in vitro; 2/Definition of an "immune phenotype" of the tumour which should be evaluated as a prognostic marker both for survival after radical surgery of localized tumours as a prognostic factor for response to immunotherapy in metastatic forms.

  4. 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.

  5. 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.

  6. 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

  7. Quantifying Adaptive Evolution in the Drosophila Immune System

    PubMed Central

    Obbard, Darren J.; Welch, John J.; Kim, Kang-Wook; Jiggins, Francis M.

    2009-01-01

    It is estimated that a large proportion of amino acid substitutions in Drosophila have been fixed by natural selection, and as organisms are faced with an ever-changing array of pathogens and parasites to which they must adapt, we have investigated the role of parasite-mediated selection as a likely cause. To quantify the effect, and to identify which genes and pathways are most likely to be involved in the host–parasite arms race, we have re-sequenced population samples of 136 immunity and 287 position-matched non-immunity genes in two species of Drosophila. Using these data, and a new extension of the McDonald-Kreitman approach, we estimate that natural selection fixes advantageous amino acid changes in immunity genes at nearly double the rate of other genes. We find the rate of adaptive evolution in immunity genes is also more variable than other genes, with a small subset of immune genes evolving under intense selection. These genes, which are likely to represent hotspots of host–parasite coevolution, tend to share similar functions or belong to the same pathways, such as the antiviral RNAi pathway and the IMD signalling pathway. These patterns appear to be general features of immune system evolution in both species, as rates of adaptive evolution are correlated between the D. melanogaster and D. simulans lineages. In summary, our data provide quantitative estimates of the elevated rate of adaptive evolution in immune system genes relative to the rest of the genome, and they suggest that adaptation to parasites is an important force driving molecular evolution. PMID:19851448

  8. Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity.

    PubMed

    Israel, Laura; Wang, Ying; Bulek, Katarzyna; Della Mina, Erika; Zhang, Zhao; Pedergnana, Vincent; Chrabieh, Maya; Lemmens, Nicole A; Sancho-Shimizu, Vanessa; Descatoire, Marc; Lasseau, Théo; Israelsson, Elisabeth; Lorenzo, Lazaro; Yun, Ling; Belkadi, Aziz; Moran, Andrew; Weisman, Leonard E; Vandenesch, François; Batteux, Frederic; Weller, Sandra; Levin, Michael; Herberg, Jethro; Abhyankar, Avinash; Prando, Carolina; Itan, Yuval; van Wamel, Willem J B; Picard, Capucine; Abel, Laurent; Chaussabel, Damien; Li, Xiaoxia; Beutler, Bruce; Arkwright, Peter D; Casanova, Jean-Laurent; Puel, Anne

    2017-02-23

    The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.

  9. Adipose-immune interactions during obesity and caloric restriction: reciprocal mechanisms regulating immunity and health span

    PubMed Central

    Dixit, Vishwa Deep

    2008-01-01

    Increasing evidence suggests a tight coupling of metabolic and immune systems. This cross-talk mediated by neuroendocrine peptides as well as numerous cytokines and chemokines is believed to be responsible for integrating energy balance to immune function. These neuroendocrine-immune interactions are heightened during the state of chronic positive energy balance, as seen during obesity, and negative energy balance caused by caloric restriction (CR). Emerging evidence suggests that obesity may be associated with an immunodeficient state and chronic inflammation, which contribute to an increased risk of premature death. The direct interactions between expanded leukocyte populations within the adipose tissue during obesity and an increased number of adipocytes within an aging lymphoid microenvironment may constitute an important adaptive or pathological response as a result of change in energy balance. In stark contrast to obesity, CR causes negative energy balance and robustly prolongs a healthy lifespan in all of the species studied to date. Therefore, the endogenous neuroendocrine-metabolic sensors elevated or suppressed as a result of changes in energy balance may offer an important mechanism in understanding the antiaging and potential immune-enhancing nature of CR. Ghrelin, one such sensor of negative energy balance, is reduced during obesity and increased by CR. Ghrelin also regulates immune function by reducing proinflammatory cytokines and promotes thymopoiesis during aging and thus, may be a new CR mimetic target. The identification of immune effects and molecular pathways used by such orexigenic metabolic factors could offer potentially novel approaches to enhance immunity and increase healthy lifespan. PMID:18579754

  10. Arginine Metabolism in Myeloid Cells Shapes Innate and Adaptive Immunity

    PubMed Central

    Rodriguez, Paulo C.; Ochoa, Augusto C.; Al-Khami, Amir A.

    2017-01-01

    Arginine metabolism has been a key catabolic and anabolic process throughout the evolution of the immune response. Accruing evidence indicates that arginine-catabolizing enzymes, mainly nitric oxide synthases and arginases, are closely integrated with the control of immune response under physiological and pathological conditions. Myeloid cells are major players that exploit the regulators of arginine metabolism to mediate diverse, although often opposing, immunological and functional consequences. In this article, we focus on the importance of arginine catabolism by myeloid cells in regulating innate and adaptive immunity. Revisiting this matter could result in novel therapeutic approaches by which the immunoregulatory nodes instructed by arginine metabolism can be targeted. PMID:28223985

  11. 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

  12. Cellular Immune Mechanisms in Malaria.

    DTIC Science & Technology

    1980-08-31

    AD-A132 480 CELLULAR IMUNE MECHANISMS IN MALARIAIUI WASHINGTON I UNIV ST LOUIS 00 SCHOOL OF MEDICINE R P UACDERUOTT 31 AUG 8o 0AMI17-78-C-8012...lupus erythematosus (15). Subsequently, a variety of other disease states have been shown to be associated with an increased incidence of...lymphocytotoxic antibodies, including inflammatory bowel disease (16) and multiple sclerosis (17). We therefore also decided to investigate sera of adult Thai

  13. Molecular mechanisms of temperature adaptation

    PubMed Central

    Bagriantsev, Sviatoslav N; Gracheva, Elena O

    2015-01-01

    Thermal perception is a fundamental physiological process pertaining to the vast majority of organisms. In vertebrates, environmental temperature is detected by the primary afferents of the somatosensory neurons in the skin, which express a ‘choir’ of ion channels tuned to detect particular temperatures. Nearly two decades of research have revealed a number of receptor ion channels that mediate the perception of several temperature ranges, but most still remain molecularly orphaned. Yet even within this well-researched realm, most of our knowledge largely pertains to two closely related species of rodents, mice and rats. While these are standard biomedical research models, mice and rats provide a limited perspective to elucidate the general principles that drive somatosensory evolution. In recent years, significant advances have been made in understanding the molecular mechanism of temperature adaptation in evolutionarily distant vertebrates and in organisms with acute thermal sensitivity. These studies have revealed the remarkable versatility of the somatosensory system and highlighted adaptations at the molecular level, which often include changes in biophysical properties of ion channels from the transient receptor potential family. Exploiting non-standard animal models has the potential to provide unexpected insights into general principles of thermosensation and thermoregulation, unachievable using the rodent model alone. PMID:25433072

  14. 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

  15. 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.

  16. A role of the adaptive immune system in glucose homeostasis

    PubMed Central

    Bronsart, Laura L; Contag, Christopher H

    2016-01-01

    Objective The immune system, including the adaptive immune response, has recently been recognized as having a significant role in diet-induced insulin resistance. In this study, we aimed to determine if the adaptive immune system also functions in maintaining physiological glucose homeostasis in the absence of diet-induced disease. Research design and methods SCID mice and immunocompetent control animals were phenotypically assessed for variations in metabolic parameters and cytokine profiles. Additionally, the glucose tolerance of SCID and immunocompetent control animals was assessed following introduction of a high-fat diet. Results SCID mice on a normal chow diet were significantly insulin resistant relative to control animals despite having less fat mass. This was associated with a significant increase in the innate immunity-stimulating cytokines granulocyte colony-stimulating factor, monocyte chemoattractant protein 1 (MCP1), and MCP3. Additionally, the SCID mouse phenotype was exacerbated in response to a high-fat diet as evidenced by the further significant progression of glucose intolerance. Conclusions These results support the notion that the adaptive immune system plays a fundamental biological role in glucose homeostasis, and that the absence of functional B and T cells results in disruption in the concentrations of various cytokines associated with macrophage proliferation and recruitment. Additionally, the absence of functional B and T cells is not protective against diet-induced pathology. PMID:27026807

  17. Prognostic value of innate and adaptive immunity in colorectal cancer.

    PubMed

    Grizzi, Fabio; Bianchi, Paolo; Malesci, Alberto; Laghi, Luigi

    2013-01-14

    Colorectal cancer (CRC) remains one of the major public health problems throughout the world. Originally depicted as a multi-step dynamical disease, CRC develops slowly over several years and progresses through cytologically distinct benign and malignant states, from single crypt lesions through adenoma, to malignant carcinoma with the potential for invasion and metastasis. Moving from histological observations since a long time, it has been recognized that inflammation and immunity actively participate in the pathogenesis, surveillance and progression of CRC. The advent of immunohistochemical techniques and of animal models has improved our understanding of the immune dynamical system in CRC. It is well known that immune cells have variable behavior controlled by complex interactions in the tumor microenvironment. Advances in immunology and molecular biology have shown that CRC is immunogenic and that host immune responses influence survival. Several lines of evidence support the concept that tumor stromal cells, are not merely a scaffold, but rather they influence growth, survival, and invasiveness of cancer cells, dynamically contributing to the tumor microenvironment, together with immune cells. Different types of immune cells infiltrate CRC, comprising cells of both the innate and adaptive immune system. A relevant issue is to unravel the discrepancy between the inhibitory effects on cancer growth exerted by the local immune response and the promoting effects on cancer proliferation, invasion, and dissemination induced by some types of inflammatory cells. Here, we sought to discuss the role played by innate and adaptive immune system in the local progression and metastasis of CRC, and the prognostic information that we can currently understand and exploit.

  18. Are the innate and adaptive immune systems setting hypertension on fire?

    PubMed

    Bomfim, Gisele F; Rodrigues, Fernanda Luciano; Carneiro, Fernando S

    2017-03-01

    Hypertension is the most common chronic cardiovascular disease and is associated with several pathological states, being an important cause of morbidity and mortality around the world. Low-grade inflammation plays a key role in hypertension and the innate and adaptive immune systems seem to contribute to hypertension development and maintenance. Hypertension is associated with vascular inflammation, increased vascular cytokines levels and infiltration of immune cells in the vasculature, kidneys and heart. However, the mechanisms that trigger inflammation and immune system activation in hypertension are completely unknown. Cells from the innate immune system express pattern recognition receptors (PRR), which detect conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) that induce innate effector mechanisms to produce endogenous signals, such as inflammatory cytokines and chemokines, to alert the host about danger. Additionally, antigen-presenting cells (APC) act as sentinels that are activated by PAMPs and DAMPs to sense the presence of the antigen/neoantigen, which ensues the adaptive immune system activation. In this context, different lymphocyte types are activated and contribute to inflammation and end-organ damage in hypertension. This review will focus on experimental and clinical evidence demonstrating the contribution of the innate and adaptive immune systems to the development of hypertension.

  19. Wakayama symposium: interface between innate and adaptive immunity in dry eye disease.

    PubMed

    Na, Kyung-Sun; Hwang, Kyu-Yeon; Lee, Hyun-Soo; Chung, So-Hyang; Mok, Jee Won; Joo, Choun-Ki

    2015-12-17

    Although the mechanism of dry eye disease is not clearly understood, it is certain that inflammation and the immune response play a major role in determining the health of the ocular surface in dry eye patients. Accurate ocular surface characterization during the early stages of dry eye disease is critical for successful treatment, because there exists no single standard, objective test to diagnose the early phase of dry eye disease. The treatment target should be direct to prevent the perpetuation of chronic inflammation and immune responses. Numerous studies have categorized dry eye disease as an autoimmune-related inflammatory disease. However, relatively little is known about how innate immune mechanisms act following a local insult, why some patients are particularly vulnerable, and why local inflammation fails to resolve in these patients. Within this review, particular attention will be given to the very early events and corresponding defense mechanism in dry eye disease. The transition from innate to adaptive immunity will also be discussed.

  20. 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.

  1. Adapting to new threats: the generation of memory by CRISPR-Cas immune systems.

    PubMed

    Heler, Robert; Marraffini, Luciano A; Bikard, David

    2014-07-01

    Clustered, regularly interspaced, short palindromic repeats (CRISPR) loci and their associated genes (cas) confer bacteria and archaea with adaptive immunity against phages and other invading genetic elements. A fundamental requirement of any immune system is the ability to build a memory of past infections in order to deal more efficiently with recurrent infections. The adaptive feature of CRISPR-Cas immune systems relies on their ability to memorize DNA sequences of invading molecules and integrate them in between the repetitive sequences of the CRISPR array in the form of 'spacers'. The transcription of a spacer generates a small antisense RNA that is used by RNA-guided Cas nucleases to cleave the invading nucleic acid in order to protect the cell from infection. The acquisition of new spacers allows the CRISPR-Cas immune system to rapidly adapt against new threats and is therefore termed 'adaptation'. Recent studies have begun to elucidate the genetic requirements for adaptation and have demonstrated that rather than being a stochastic process, the selection of new spacers is influenced by several factors. We review here our current knowledge of the CRISPR adaptation mechanism.

  2. 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.

  3. Suppression of immune response to Listeria monocytogenes: mechanism(s) of immune complex suppression.

    PubMed Central

    Virgin, H W; Wittenberg, G F; Bancroft, G J; Unanue, E R

    1985-01-01

    We have investigated possible mechanisms underlying immune complex suppression of resistance to Listeria monocytogenes. Inhibition of resistance was found when immune complexes were formed in vivo in immune mice or in nonimmune mice adoptively transferred with specific antibody. Suppression was also found when nonimmune mice were injected with immune complexes preformed in vitro. We investigated the role of complement by decomplementing mice with cobra venom factor purified by high-pressure liquid chromatography. Complete depletion of serum C3 did not eliminate immune complex suppression of resistance to L. monocytogenes, suggesting that complement activation is not required for immune complex suppression. Infection-induced changes in the surface phenotype and functional properties of macrophages from normal and immune complex-suppressed mice were also investigated. Macrophage expression of both H-2K and Ia molecules increased during the response of normal mice to L. monocytogenes. However, these changes were not found in immune complex-suppressed mice. In contrast, membrane interleukin 1 expression was increased in macrophages from suppressed mice compared with macrophages from normal mice. Macrophages from L. monocytogenes-infected normal and immune complex-suppressed mice expressed cytotoxicity against tumor cells in vitro. We conclude that immune complexes do not inhibit resistance to L. monocytogenes by activation of complement or decreasing macrophage cytotoxic activity. Rather, defects in Ia expression by macrophages from suppressed mice might be one component responsible for immune complex suppression of resistance to L. monocytogenes. PMID:3932204

  4. The Adaptive Immune System of Haloferax volcanii.

    PubMed

    Maier, Lisa-Katharina; Dyall-Smith, Mike; Marchfelder, Anita

    2015-02-16

    To fight off invading genetic elements, prokaryotes have developed an elaborate defence system that is both adaptable and heritable-the CRISPR-Cas system (CRISPR is short for: clustered regularly interspaced short palindromic repeats and Cas: CRISPR associated). Comprised of proteins and multiple small RNAs, this prokaryotic defence system is present in 90% of archaeal and 40% of bacterial species, and enables foreign intruders to be eliminated in a sequence-specific manner. There are three major types (I-III) and at least 14 subtypes of this system, with only some of the subtypes having been analysed in detail, and many aspects of the defence reaction remaining to be elucidated. Few archaeal examples have so far been analysed. Here we summarize the characteristics of the CRISPR-Cas system of Haloferax volcanii, an extremely halophilic archaeon originally isolated from the Dead Sea. It carries a single CRISPR-Cas system of type I-B, with a Cascade like complex composed of Cas proteins Cas5, Cas6b and Cas7. Cas6b is essential for CRISPR RNA (crRNA) maturation but is otherwise not required for the defence reaction. A systematic search revealed that six protospacer adjacent motif (PAM) sequences are recognised by the Haloferax defence system. For successful invader recognition, a non-contiguous seed sequence of 10 base-pairs between the crRNA and the invader is required.

  5. Immune mechanisms in beryllium lung disease

    SciTech Connect

    Deodhar, S.D.; Barna, B.P. )

    1991-03-01

    The role of the immune system in the pathogenesis of beryllium lung disease has been suspected for years. The observation of cutaneous hypersensitivity to beryllium led to the development of the lymphocyte blast transformation test; the test clearly distinguishes between healthy subjects, who show little or no blast transformation response, and patients with beryllium lung disease, who demonstrate significant responses. The degree of blast transformation also correlates with the severity of the clinical disease. Animal studies have demonstrated the importance of histocompatibility antigens in development of the disease, and support the participation of cellular immune mechanisms.22 references.

  6. Drought Adaptation Mechanisms Should Guide Experimental Design.

    PubMed

    Gilbert, Matthew E; Medina, Viviana

    2016-08-01

    The mechanism, or hypothesis, of how a plant might be adapted to drought should strongly influence experimental design. For instance, an experiment testing for water conservation should be distinct from a damage-tolerance evaluation. We define here four new, general mechanisms for plant adaptation to drought such that experiments can be more easily designed based upon the definitions. A series of experimental methods are suggested together with appropriate physiological measurements related to the drought adaptation mechanisms. The suggestion is made that the experimental manipulation should match the rate, length, and severity of soil water deficit (SWD) necessary to test the hypothesized type of drought adaptation mechanism.

  7. gammadelta T cells link innate and adaptive immune responses.

    PubMed

    Holtmeier, Wolfgang; Kabelitz, Dieter

    2005-01-01

    While most T cells use a CD3-associated alpha/beta T cell receptor as antigen recognition structure, a second population of T cells expresses the alternative gamma/delta T cell receptor. gamma/delta T cells are a minor population in the peripheral blood but constitute a major population among intestinal intraepithelial lymphocytes. Most gamma/delta T cells recognize ligands which are fundamentally different from the short peptides that are seen by alpha/beta T cells in the context of MHC class I or class II molecules. Thus, human Vdelta2 T cells recognize small bacterial phosphoantigens, alkylamines and synthetic aminobisphosphonates, whereas Vdelta1 T cells recognize stress-inducible MHC-related molecules MICA/B as well as several other ligands. At the functional level, gamma/delta T cells rapidly produce a variety of cytokines and usually exert potent cytotoxic activity, also towards many tumor cells. In this article, we discuss the role of gamma/delta T cells as a bridge between the innate and the adaptive immune system, based on the interpretation that gamma/delta T cells use their T cell receptor as a pattern recognition receptor. Our increasing understanding of the ligand recognition and activation mechanisms of gamma/delta T cells also opens new perspectives for the development of gamma/delta T cell-based immunotherapies.

  8. Modular Activating Receptors in Innate and Adaptive Immunity.

    PubMed

    Berry, Richard; Call, Matthew E

    2017-03-14

    Triggering of cell-mediated immunity is largely dependent on the recognition of foreign or abnormal molecules by a myriad of cell surface-bound receptors. Many activating immune receptors do not possess any intrinsic signaling capacity but instead form noncovalent complexes with one or more dimeric signaling modules that communicate with a common set of kinases to initiate intracellular information-transfer pathways. This modular architecture, where the ligand binding and signaling functions are detached from one another, is a common theme that is widely employed throughout the innate and adaptive arms of immune systems. The evolutionary advantages of this highly adaptable platform for molecular recognition are visible in the variety of ligand-receptor interactions that can be linked to common signaling pathways, the diversification of receptor modules in response to pathogen challenges, and the amplification of cellular responses through incorporation of multiple signaling motifs. Here we provide an overview of the major classes of modular activating immune receptors and outline the current state of knowledge regarding how these receptors assemble, recognize their ligands, and ultimately trigger intracellular signal transduction pathways that activate immune cell effector functions.

  9. Innate and Adaptive Immunity in Calcific Aortic Valve Disease.

    PubMed

    Mathieu, Patrick; Bouchareb, Rihab; Boulanger, Marie-Chloé

    2015-01-01

    Calcific aortic valve disease (CAVD) is the most common heart valve disorder. CAVD is a chronic process characterized by a pathologic mineralization of valve leaflets. Ectopic mineralization of the aortic valve involves complex relationships with immunity. Studies have highlighted that both innate and adaptive immunity play a role in the development of CAVD. In this regard, accumulating evidence indicates that fibrocalcific remodelling of the aortic valve is associated with activation of the NF-κB pathway. The expression of TNF-α and IL-6 is increased in human mineralized aortic valves and promotes an osteogenic program as well as the mineralization of valve interstitial cells (VICs), the main cellular component of the aortic valve. Different factors, including oxidized lipid species, activate the innate immune response through the Toll-like receptors. Moreover, VICs express 5-lipoxygenase and therefore produce leukotrienes, which may amplify the inflammatory response in the aortic valve. More recently, studies have emphasized that an adaptive immune response is triggered during CAVD. Herein, we are reviewing the link between the immune response and the development of CAVD and we have tried, whenever possible, to keep a translational approach.

  10. Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses.

    PubMed

    Mahanty, Siddhartha; Hutchinson, Karen; Agarwal, Sudhanshu; McRae, Michael; Rollin, Pierre E; Pulendran, Bali

    2003-03-15

    Acute infection of humans with Ebola and Lassa viruses, two principal etiologic agents of hemorrhagic fevers, often results in a paradoxical pattern of immune responses: early infection, characterized by an outpouring of inflammatory mediators such as TNF-alpha, IL-1 beta, and IL-6, vs late stage infections, which are associated with poor immune responses. The mechanisms underlying these diverse outcomes are poorly understood. In particular, the role played by cells of the innate immune system, such as dendritic cells (DC), is not known. In this study, we show that Ebola and Lassa viruses infect human monocyte-derived DC and impair their function. Monocyte-derived DC exposed to either virus fail to secrete proinflammatory cytokines, do not up-regulate costimulatory molecules, and are poor stimulators of T cells. These data represent the first evidence for a mechanism by which Ebola and Lassa viruses target DC to impair adaptive immunity.

  11. Insights on adaptive and innate immunity in canine leishmaniosis.

    PubMed

    Hosein, Shazia; Blake, Damer P; Solano-Gallego, Laia

    2017-01-01

    Canine leishmaniosis (CanL) is caused by the parasite Leishmania infantum and is a systemic disease, which can present with variable clinical signs, and clinicopathological abnormalities. Clinical manifestations can range from subclinical infection to very severe systemic disease. Leishmaniosis is categorized as a neglected tropical disease and the complex immune responses associated with Leishmania species makes therapeutic treatments and vaccine development challenging for both dogs and humans. In this review, we summarize innate and adaptive immune responses associated with L. infantum infection in dogs, and we discuss the problems associated with the disease as well as potential solutions and the future direction of required research to help control the parasite.

  12. Adaptive diagnosis of the bilinear mechanical systems

    NASA Astrophysics Data System (ADS)

    Gelman, L.; Gorpinich, S.; Thompson, C.

    2009-07-01

    A generic adaptive approach is proposed for diagnosis of the bilinear mechanical systems. The approach adapts the free oscillation method for bilinearity diagnosis of mechanical systems. The expediency of the adaptation is proved for a recognition feature, the decrement of the free oscillations. The developed adaptation consists of variation of the adaptive likelihood ratio of the decrement with variation of the resonance frequency of the bilinear system. It is shown that in the cases of the frequency-independent and the frequency-dependent internal damping, the adaptation is expedient. To investigate effectiveness of the adaptation in these cases, a numerical simulation was carried out. The simulation results show that use of the adaptation increases the total probability of the correct diagnosis of system bilinearity.

  13. Molecular mechanisms of CRISPR-mediated microbial immunity.

    PubMed

    Gasiunas, Giedrius; Sinkunas, Tomas; Siksnys, Virginijus

    2014-02-01

    Bacteriophages (phages) infect bacteria in order to replicate and burst out of the host, killing the cell, when reproduction is completed. Thus, from a bacterial perspective, phages pose a persistent lethal threat to bacterial populations. Not surprisingly, bacteria evolved multiple defense barriers to interfere with nearly every step of phage life cycles. Phages respond to this selection pressure by counter-evolving their genomes to evade bacterial resistance. The antagonistic interaction between bacteria and rapidly diversifying viruses promotes the evolution and dissemination of bacteriophage-resistance mechanisms in bacteria. Recently, an adaptive microbial immune system, named clustered regularly interspaced short palindromic repeats (CRISPR) and which provides acquired immunity against viruses and plasmids, has been identified. Unlike the restriction–modification anti-phage barrier that subjects to cleavage any foreign DNA lacking a protective methyl-tag in the target site, the CRISPR–Cas systems are invader-specific, adaptive, and heritable. In this review, we focus on the molecular mechanisms of interference/immunity provided by different CRISPR–Cas systems.

  14. The role of the innate and adaptive immune responses in Acanthamoeba keratitis.

    PubMed

    Niederkorn, Jerry Y

    2002-01-01

    Infections of the corneal surface are an important cause of blindness. Protozoal, viral, bacterial, and helminthic infections of the cornea account for up to 9 million cases of corneal blindness. Free-living amoebae of the genus Acanthamoeba produce a progressive infection of the cornea called Acanthamoeba keratitis. Disease is usually transmitted by Acanthamoeba trophozoites bound to soft contact lenses. Infection of the cornea is initiated when the parasite binds to the corneal epithelial surface. Recrudescence can occur and suggests that the adaptive immune response is not aroused by corneal Acanthamoeba infections. Systemic immunization with Acanthamoeba antigens elicits robust Th1 cell-mediated immunity and serum IgG antibody, yet fails to prevent the development of Acanthamoeba keratitis. However, immunization via mucosal surfaces induces anti-Acanthamoeba IgA antibodies in the tears and provides solid protection against the development of Acanthamoeba keratitis. Unlike other immune effector mechanisms that rely on cytolysis, inflammation, release of toxic molecules, or the induction of host cell death, the adaptive immune apparatus prevents Acanthamoeba infections of the cornea by simply preventing the attachment of the parasite to the epithelial surface. The beauty of this mechanism lies in its exquisite simplicity and efficacy.

  15. Immune and Neuroendocrine Mechanisms of Stress Vulnerability and Resilience.

    PubMed

    Ménard, Caroline; Pfau, Madeline L; Hodes, Georgia E; Russo, Scott J

    2017-01-01

    Diagnostic criteria for mood disorders including major depressive disorder (MDD) largely ignore biological factors in favor of behavioral symptoms. Compounding this paucity of psychiatric biomarkers is a need for therapeutics to adequately treat the 30-50% of MDD patients who are unresponsive to traditional antidepressant medications. Interestingly, MDD is highly prevalent in patients suffering from chronic inflammatory conditions, and MDD patients exhibit higher levels of circulating pro-inflammatory cytokines. Together, these clinical findings suggest a role for the immune system in vulnerability to stress-related psychiatric illness. A growing body of literature also implicates the immune system in stress resilience and coping. In this review, we discuss the mechanisms by which peripheral and central immune cells act on the brain to affect stress-related neurobiological and neuroendocrine responses. We specifically focus on the roles of pro-inflammatory cytokine signaling, peripheral monocyte infiltration, microglial activation, and hypothalamic-pituitary-adrenal axis hyperactivity in stress vulnerability. We also highlight recent evidence suggesting that adaptive immune responses and treatment with immune modulators (exogenous glucocorticoids, humanized antibodies against cytokines) may decrease depressive symptoms and thus represent an attractive alternative to the current antidepressant treatments.

  16. Two forms of adaptive immunity in vertebrates: similarities and differences.

    PubMed

    Kasahara, Masanori; Sutoh, Yoichi

    2014-01-01

    Unlike jawed vertebrates that use T-cell and B-cell receptors for antigen recognition, jawless vertebrates represented by lampreys and hagfish use variable lymphocyte receptors (VLRs) as antigen receptors. VLRs generate diversity comparable to that of gnathostome antigen receptors by assembling variable leucine-rich repeat modules. The discovery of VLR has revolutionized our understanding of how adaptive immunity emerged and highlighted the differences between the adaptive immune systems (AISs) of jawed and jawless vertebrates. However, emerging evidence also indicates that their AISs have much in common. Particularly striking is the conservation of lymphocyte lineages. The basic architecture of the AIS including the dichotomy of lymphocytes appears to have been established in a common ancestor of jawed and jawless vertebrates. We review here the current knowledge on the AIS of jawless vertebrates, emphasizing both the similarities to and differences from the AIS of jawed vertebrates.

  17. Bridging Innate and Adaptive Antitumor Immunity Targeting Glycans

    PubMed Central

    Pashov, Anastas; Monzavi-Karbassi, Bejatolah; Raghava, Gajendra P. S.; Kieber-Emmons, Thomas

    2010-01-01

    Effective immunotherapy for cancer depends on cellular responses to tumor antigens. The role of major histocompatibility complex (MHC) in T-cell recognition and T-cell receptor repertoire selection has become a central tenet in immunology. Structurally, this does not contradict earlier findings that T-cells can differentiate between small hapten structures like simple glycans. Understanding T-cell recognition of antigens as defined genetically by MHC and combinatorially by T cell receptors led to the “altered self” hypothesis. This notion reflects a more fundamental principle underlying immune surveillance and integrating evolutionarily and mechanistically diverse elements of the immune system. Danger associated molecular patterns, including those generated by glycan remodeling, represent an instance of altered self. A prominent example is the modification of the tumor-associated antigen MUC1. Similar examples emphasize glycan reactivity patterns of antigen receptors as a phenomenon bridging innate and adaptive but also humoral and cellular immunity and providing templates for immunotherapies. PMID:20617150

  18. Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response

    PubMed Central

    Liliensiek, Birgit; Weigand, Markus A.; Bierhaus, Angelika; Nicklas, Werner; Kasper, Michael; Hofer, Stefan; Plachky, Jens; Gröne, Herman-Josef; Kurschus, Florian C.; Schmidt, Ann Marie; Yan, Shi Du; Martin, Eike; Schleicher, Erwin; Stern, David M.; Hämmerling, Günter J.; Nawroth, Peter P.; Arnold, Bernd

    2004-01-01

    While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation. PMID:15173891

  19. A novel mechanism of cone photoreceptor adaptation.

    PubMed

    Howlett, Marcus H C; Smith, Robert G; Kamermans, Maarten

    2017-04-01

    An animal's ability to survive depends on its sensory systems being able to adapt to a wide range of environmental conditions, by maximizing the information extracted and reducing the noise transmitted. The visual system does this by adapting to luminance and contrast. While luminance adaptation can begin at the retinal photoreceptors, contrast adaptation has been shown to start at later stages in the retina. Photoreceptors adapt to changes in luminance over multiple time scales ranging from tens of milliseconds to minutes, with the adaptive changes arising from processes within the phototransduction cascade. Here we show a new form of adaptation in cones that is independent of the phototransduction process. Rather, it is mediated by voltage-gated ion channels in the cone membrane and acts by changing the frequency response of cones such that their responses speed up as the membrane potential modulation depth increases and slow down as the membrane potential modulation depth decreases. This mechanism is effectively activated by high-contrast stimuli dominated by low frequencies such as natural stimuli. However, the more generally used Gaussian white noise stimuli were not effective since they did not modulate the cone membrane potential to the same extent. This new adaptive process had a time constant of less than a second. A critical component of the underlying mechanism is the hyperpolarization-activated current, Ih, as pharmacologically blocking it prevented the long- and mid- wavelength sensitive cone photoreceptors (L- and M-cones) from adapting. Consistent with this, short- wavelength sensitive cone photoreceptors (S-cones) did not show the adaptive response, and we found they also lacked a prominent Ih. The adaptive filtering mechanism identified here improves the information flow by removing higher-frequency noise during lower signal-to-noise ratio conditions, as occurs when contrast levels are low. Although this new adaptive mechanism can be driven by

  20. Boosting Adaptive Immunity: A New Role for PAFR Antagonists

    PubMed Central

    Koga, Marianna M.; Bizzarro, Bruna; Sá-Nunes, Anderson; Rios, Francisco J.; Jancar, Sonia

    2016-01-01

    We have previously shown that the Platelet-Activating Factor Receptor (PAFR) engagement in murine macrophages and dendritic cells (DCs) promotes a tolerogenic phenotype reversed by PAFR-antagonists treatment in vitro. Here, we investigated whether a PAFR antagonist would modulate the immune response in vivo. Mice were subcutaneously injected with OVA or OVA with PAFR-antagonist WEB2170 on days 0 and 7. On day 14, OVA–specific IgG2a and IgG1 were measured in the serum. The presence of WEB2170 during immunization significantly increased IgG2a without affecting IgG1 levels. When WEB2170 was added to OVA in complete Freund’s adjuvant, enhanced IgG2a but not IgG1 production was also observed, and CD4+ FoxP3+ T cell frequency in the spleen was reduced compared to mice immunized without the antagonist. Similar results were observed in PAFR-deficient mice, along with increased Tbet mRNA expression in the spleen. Additionally, bone marrow-derived DCs loaded with OVA were transferred into naïve mice and their splenocytes were co-cultured with fresh OVA-loaded DCs. CD4+ T cell proliferation was higher in the group transferred with DCs treated with the PAFR-antagonist. We propose that the activation of PAFR by ligands present in the site of immunization is able to fine-tune the adaptive immune response. PMID:27966635

  1. hnRNP I regulates neonatal immune adaptation and prevents colitis and colorectal cancer

    PubMed Central

    Liang, Feng

    2017-01-01

    The intestinal epithelium plays a critical role in host-microbe homeostasis by sensing gut microbes and subsequently initiating proper immune responses. During the neonatal stage, the intestinal epithelium is under immune repression, allowing the transition for newborns from a relatively sterile intra-uterine environment to one that is rich in foreign antigens. The mechanism underlying such immune repression remains largely unclear, but involves downregulation of IRAK1 (interleukin-1 receptor-associated kinase), an essential component of toll-like receptor-mediated NF-κB signaling. We report here that heterogeneous nuclear ribonucleoprotein I (hnRNPI), an RNA binding protein, is essential for regulating neonatal immune adaptation. We generated a mouse model in which hnRNPI is ablated specifically in the intestinal epithelial cells, and characterized intestinal defects in the knockout mice. We found that loss of hnRNPI function in mouse intestinal epithelial cells results in early onset of spontaneous colitis followed by development of invasive colorectal cancer. Strikingly, the epithelium-specific hnRNPI knockout neonates contain aberrantly high IRAK1 protein levels in the colons and fail to develop immune tolerance to environmental microbes. Our results demonstrate that hnRNPI plays a critical role in establishing neonatal immune adaptation and preventing colitis and colorectal cancer. PMID:28296893

  2. 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

  3. Generation of individual diversity: a too neglected fundamental property of adaptive immune system.

    PubMed

    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.

  4. Epileptic encephalitis: the role of the innate and adaptive immune system.

    PubMed

    Bauer, Jan; Vezzani, Annamaria; Bien, Christian G

    2012-05-01

    Seizures are a prominent clinical feature of encephalitis. Recent data suggest the adaptive as well as innate immune system to be involved directly in the pathomechanism of epileptogenesis. Cytotoxic T-cells and antibody-mediated complement activation are major components of the adaptive immune system, which can induce neurodegeneration, thereby probably contributing to epileptic encephalitis. The innate immune system operates via interleukin-1 and toll-like receptor-associated mechanisms and was shown to play a direct role in epileptogenesis. Here, we review neuropathology hallmarks of various encephalitis conditions such as Rasmussen encephalitis (RE) but also introduce the more recently discovered antibody-associated voltage-gated potassium channel complex (VGKC), N-methyl-D-aspartate receptor (NMDAR) or glutamic acid decarboxylase (GAD) 65 encephalitides. Neuropathological investigations are used to determine specific cellular components and molecular mechanisms used by the immune system to provoke neurodegeneration and to promote epileptogenesis. Based on recent findings, we propose concepts for the stratification of epileptic encephalitis. Knowledge of the role of the innate immunity has already translated into clinical treatment strategies and may help to discover novel drug targets for these epileptic disorders.

  5. Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

    PubMed Central

    Price, Patricia; Murdoch, David M.; Agarwal, Upasna; Lewin, Sharon R.; Elliott, Julian H.; French, Martyn A.

    2009-01-01

    Summary: Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses. PMID:19822893

  6. Marijuana use and brain immune mechanisms.

    PubMed

    Cabral, Guy A; Jamerson, Melissa

    2014-01-01

    The recreational smoking of marijuana, or Cannabis sativa, has become widespread, including among adolescents. Marijuana contains a class of compounds known as phytocannabinoids that include cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC). THC is the major psychoactive component in marijuana, but also exhibits immunosuppressive activity. CBD, while not psychotropic, also modulates immune function, but its mechanism of action appears to differ from that of THC. Since both compounds are highly lipophilic, they readily passage the blood-brain barrier and access the central nervous system. Since CBD is not psychotropic, it has been considered as a candidate therapeutic compound for ablating neuropathological processes characterized by hyperinflammation. However, an unresolved question centers around the impact of these compounds on immune-competent cells within the CNS in relation to susceptibility to infection. There are accumulating data indicating that THC inhibits the migratory capability of macrophage-like cells resident in the CNS, such as microglia, toward nodes of microbial invasion. Furthermore, phytocannabinoids have been reported to exert developmental and long-term effects on the immune system suggesting that exposure to these substances during an early stage in life has the potential to alter the fundamental neuroimmune response to select microbial agents in the adult.

  7. Immune restoration diseases reflect diverse immunopathological mechanisms.

    PubMed

    Price, Patricia; Murdoch, David M; Agarwal, Upasna; Lewin, Sharon R; Elliott, Julian H; French, Martyn A

    2009-10-01

    Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

  8. Pathogenesis of NEC: Role of the innate and adaptive immune response.

    PubMed

    Denning, Timothy W; Bhatia, Amina M; Kane, Andrea F; Patel, Ravi M; Denning, Patricia W

    2017-02-01

    Necrotizing enterocolitis (NEC) is a devastating disease in premature infants with high case fatality and significant morbidity among survivors. Immaturity of intestinal host defenses predisposes the premature infant gut to injury. An abnormal bacterial colonization pattern with a deficiency of commensal bacteria may lead to a further breakdown of these host defense mechanisms, predisposing the infant to NEC. Here, we review the role of the innate and adaptive immune system in the pathophysiology of NEC.

  9. CRISPR-Cas adaptation: insights into the mechanism of action.

    PubMed

    Amitai, Gil; Sorek, Rotem

    2016-02-01

    Since the first demonstration that CRISPR-Cas systems provide bacteria and archaea with adaptive immunity against phages and plasmids, numerous studies have yielded key insights into the molecular mechanisms governing how these systems attack and degrade foreign DNA. However, the molecular mechanisms underlying the adaptation stage, in which new immunological memory is formed, have until recently represented a major unresolved question. In this Progress article, we discuss recent discoveries that have shown both how foreign DNA is identified by the CRISPR-Cas adaptation machinery and the molecular basis for its integration into the chromosome to form an immunological memory. Furthermore, we describe the roles of each of the specific CRISPR-Cas components that are involved in memory formation, and consider current models for their evolutionary origin.

  10. Future directions in bladder cancer immunotherapy: towards adaptive immunity.

    PubMed

    Smith, Sean G; Zaharoff, David A

    2016-01-01

    The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed.

  11. Soft Thermal Sensor with Mechanical Adaptability.

    PubMed

    Yang, Hui; Qi, Dianpeng; Liu, Zhiyuan; Chandran, Bevita K; Wang, Ting; Yu, Jiancan; Chen, Xiaodong

    2016-11-01

    A soft thermal sensor with mechanical adaptability is fabricated by the combination of single-wall carbon nanotubes with carboxyl groups and self-healing polymers. This study demonstrates that this soft sensor has excellent thermal response and mechanical adaptability. It shows tremendous promise for improving the service life of soft artificial-intelligence robots and protecting thermally sensitive electronics from the risk of damage by high temperature.

  12. The microbiota in adaptive immune homeostasis and disease.

    PubMed

    Honda, Kenya; Littman, Dan R

    2016-07-07

    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.

  13. 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

  14. Deciphering the Adaptive Immune Response to Ovarian Cancer

    DTIC Science & Technology

    2014-10-01

    Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C, Stuart JM. The Cancer Genome Atlas Pan-Cancer analysis...Holt, Ph.D., John Webb Ph.D., Peter Watson, M.D. Title of Project: Deciphering the Adaptive Immune Response to Ovarian Cancer INTRODUCTION...Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, Yau C, Laird PW, Ding L, Zhang W, Mills GB, Kucherlapati R, Mardis ER

  15. Innate and Adaptive Immune Response to Apoptotic Cells

    PubMed Central

    Peng, YuFeng; Martin, David A; Kenkel, Justin; Zhang, Kang; Ogden, Carol Anne; Elkon, Keith B.

    2007-01-01

    The immune system is constantly exposed to dying cells, most of which arise during central tolerance and from effete circulating immune cells. Under homeostatic conditions, phagocytes (predominantly macrophages and dendritic cells) belonging to the innate immune system, rapidly ingest cells and their debris. Apoptotic cell removal requires recognition of altered self on the apoptotic membrane, a process which is facilitated by natural antibodies and serum opsonins. Recognition, may be site and context specific. Uptake and ingestion of apoptotic cells promotes an immunosuppressive environment that avoids inflammatory responses to self antigens. However, it does not preclude a T cell response and it is likely that constant exposure to self antigen, particularly by immature dendritic cells, leads to T cell tolerance. Tolerance occurs by several different mechanisms including anergy and deletion (for CD8+ T cells) and induction of T regulatory cells (for CD4+ T cells). Failed apoptotic cell clearance promotes immune responses to self antigens, especially when the cellular contents are leaked from the cell (necrosis). Inflammatory responses may be induced by nucleic acid stimulation of toll like receptors and other immune sensors, specific intracellular proteins and non protein (uric acid) stimulation of inflammasomes. PMID:17888627

  16. 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

    2016-02-17

    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.

  17. Microglia mechanics: immune activation alters traction forces and durotaxis

    PubMed Central

    Bollmann, Lars; Koser, David E.; Shahapure, Rajesh; Gautier, Hélène O. B.; Holzapfel, Gerhard A.; Scarcelli, Giuliano; Gather, Malte C.; Ulbricht, Elke; Franze, Kristian

    2015-01-01

    Microglial cells are key players in the primary immune response of the central nervous system. They are highly active and motile cells that chemically and mechanically interact with their environment. While the impact of chemical signaling on microglia function has been studied in much detail, the current understanding of mechanical signaling is very limited. When cultured on compliant substrates, primary microglial cells adapted their spread area, morphology, and actin cytoskeleton to the stiffness of their environment. Traction force microscopy revealed that forces exerted by microglia increase with substrate stiffness until reaching a plateau at a shear modulus of ~5 kPa. When cultured on substrates incorporating stiffness gradients, microglia preferentially migrated toward stiffer regions, a process termed durotaxis. Lipopolysaccharide-induced immune-activation of microglia led to changes in traction forces, increased migration velocities and an amplification of durotaxis. We finally developed a mathematical model connecting traction forces with the durotactic behavior of migrating microglial cells. Our results demonstrate that microglia are susceptible to mechanical signals, which could be important during central nervous system development and pathologies. Stiffness gradients in tissue surrounding neural implants such as electrodes, for example, could mechanically attract microglial cells, thus facilitating foreign body reactions detrimental to electrode functioning. PMID:26441534

  18. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines.

    PubMed

    Blok, Bastiaan A; Arts, Rob J W; van Crevel, Reinout; Benn, Christine Stabell; Netea, Mihai G

    2015-09-01

    An increasing body of evidence shows that the innate immune system has adaptive characteristics that involve a heterologous memory of past insults. Both experimental models and proof-of-principle clinical trials show that innate immune cells, such as monocytes, macrophages, and NK cells, can provide protection against certain infections in vaccination models independently of lymphocytes. This process is regulated through epigenetic reprogramming of innate immune cells and has been termed "trained immunity." It has been hypothesized that induction of trained immunity is responsible for the protective, nonspecific effects induced by vaccines, such as BCG, measles vaccination, and other whole-microorganism vaccines. In this review, we will present the mechanisms of trained immunity responsible for the long-lasting effects of vaccines on the innate immune system.

  19. Immune Mechanisms Linking Obesity and Preeclampsia

    PubMed Central

    Spradley, Frank T.; Palei, Ana C.; Granger, Joey P.

    2015-01-01

    Preeclampsia (PE) is characterized by hypertension occurring after the twentieth week of pregnancy. It is a significant contributor to maternal and perinatal morbidity and mortality in developing countries and its pervasiveness is increasing within developed countries including the USA. However, the mechanisms mediating the pathogenesis of this maternal disorder and its rising prevalence are far from clear. A major theory with strong experimental evidence is that placental ischemia, resulting from inappropriate remodeling and widening of the maternal spiral arteries, stimulates the release of soluble factors from the ischemic placenta causing maternal endothelial dysfunction and hypertension. Aberrant maternal immune responses and inflammation have been implicated in each of these stages in the cascade leading to PE. Regarding the increased prevalence of this disease, it is becoming increasingly evident from epidemiological data that obesity, which is a state of chronic inflammation in itself, increases the risk for PE. Although the specific mechanisms whereby obesity increases the rate of PE are unclear, there are strong candidates including activated macrophages and natural killer cells within the uterus and placenta and activation in the periphery of T helper cells producing cytokines including TNF-α, IL-6 and IL-17 and the anti-angiogenic factor sFlt-1 and B cells producing the agonistic autoantibodies to the angiotensin type 1 receptor (AT1-aa). This review will focus on the immune mechanisms that have been implicated in the pathogenesis of hypertension in PE with an emphasis on the potential importance of inflammatory factors in the increased risk of developing PE in obese pregnancies. PMID:26569331

  20. Immune-mediated mechanisms influencing the efficacy of anticancer therapies.

    PubMed

    Coffelt, Seth B; de Visser, Karin E

    2015-04-01

    Conventional anticancer therapies, such as chemotherapy, radiotherapy, and targeted therapy, are designed to kill cancer cells. However, the efficacy of anticancer therapies is not only determined by their direct effects on cancer cells but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit several changes in immune-related parameters including the composition, phenotype, and function of immune cells. Here we discuss the impact of innate and adaptive immune cells on the success of anticancer therapy. In this context we examine the opportunities to exploit host immune responses to boost tumor clearing, and highlight the challenges facing the treatment of advanced metastatic disease.

  1. 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...

  2. Living in an adaptive world: Genomic dissection of the genus Homo and its immune response.

    PubMed

    Quach, Hélène; Quintana-Murci, Lluis

    2017-04-03

    More than a decade after the sequencing of the human genome, a deluge of genome-wide population data are generating a portrait of human genetic diversity at an unprecedented level of resolution. Genomic studies have provided new insight into the demographic and adaptive history of our species, Homo sapiens, including its interbreeding with other hominins, such as Neanderthals, and the ways in which natural selection, in its various guises, has shaped genome diversity. These studies, combined with functional genomic approaches, such as the mapping of expression quantitative trait loci, have helped to identify genes, functions, and mechanisms of prime importance for host survival and involved in phenotypic variation and differences in disease risk. This review summarizes new findings in this rapidly developing field, focusing on the human immune response. We discuss the importance of defining the genetic and evolutionary determinants driving immune response variation, and highlight the added value of population genomic approaches in settings relevant to immunity and infection.

  3. Intradermal naked plasmid DNA immunization: mechanisms of action.

    PubMed

    Elnekave, Mazal; Furmanov, Karina; Hovav, Avi-Hai

    2011-08-01

    Plasmid DNA is a promising vaccine modality that is regularly examined in prime-boost immunization regimens. Recent advances in skin immunity increased our understanding of the sophisticated cutaneous immune network, which revived scientific interest in delivering vaccines to the skin. Intradermal administration of plasmid DNA via needle injection is a simple and inexpensive procedure that exposes the plasmid and its encoded antigen to the dermal immune surveillance system. This triggers unique mechanisms for eliciting local and systemic immunity that can confer protection against pathogens and tumors. Understanding the mechanisms of intradermal plasmid DNA immunization is essential for enhancing and modulating its immunogenicity. With regard to vaccination, this is of greater importance as this routine injection technique is highly desirable for worldwide immunization. This article will focus on the current understanding of the mechanisms involved in antigen expression and presentation during primary and secondary syringe and needle intradermal plasmid DNA immunization.

  4. 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.

  5. Innate and adaptive immune responses against Staphylococcus aureus skin infections.

    PubMed

    Krishna, Sheila; Miller, Lloyd S

    2012-03-01

    Staphylococcus aureus is an important human pathogen that is responsible for the vast majority of bacterial skin and soft tissue infections in humans. S. aureus can also become more invasive and cause life-threatening infections such as bacteremia, pneumonia, abscesses of various organs, meningitis, osteomyelitis, endocarditis, and sepsis. These infections represent a major public health threat due to the enormous numbers of these infections and the widespread emergence of methicillin-resistant S. aureus (MRSA) strains. MSRA is endemic in hospitals worldwide and is rapidly spreading throughout the normal human population in the community. The increasing frequency of MRSA infections has complicated treatment as these strains are more virulent and are increasingly becoming resistant to multiple different classes of antibiotics. The important role of the immune response against S. aureus infections cannot be overemphasized as humans with certain genetic and acquired immunodeficiency disorders are at an increased risk for infection. Understanding the cutaneous immune responses against S. aureus is essential as most of these infections occur or originate from a site of infection or colonization of the skin and mucosa. This review will summarize the innate immune responses against S. aureus skin infections, including antimicrobial peptides that have direct antimicrobial activity against S. aureus as well as pattern recognition receptors and proinflammatory cytokines that promote neutrophil abscess formation in the skin, which is required for bacterial clearance. Finally, we will discuss the recent discoveries involving IL-17-mediated responses, which provide a key link between cutaneous innate and adaptive immune responses against S. aureus skin infections.

  6. 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.

  7. 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

  8. 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

  9. Borrelia burgdorferi Manipulates Innate and Adaptive Immunity to Establish Persistence in Rodent Reservoir Hosts

    PubMed Central

    Tracy, Karen E.; Baumgarth, Nicole

    2017-01-01

    Borrelia burgdorferi sensu lato species complex is capable of establishing persistent infections in a wide variety of species, particularly rodents. Infection is asymptomatic or mild in most reservoir host species, indicating successful co-evolution of the pathogen with its natural hosts. However, infected humans and other incidental hosts can develop Lyme disease, a serious inflammatory syndrome characterized by tissue inflammation of joints, heart, muscles, skin, and CNS. Although B. burgdorferi infection induces both innate and adaptive immune responses, they are ultimately ineffective in clearing the infection from reservoir hosts, leading to bacterial persistence. Here, we review some mechanisms by which B. burgdorferi evades the immune system of the rodent host, focusing in particular on the effects of innate immune mechanisms and recent findings suggesting that T-dependent B cell responses are subverted during infection. A better understanding of the mechanisms causing persistence in rodents may help to increase our understanding of the pathogenesis of Lyme disease and ultimately aid in the development of therapies that support effective clearance of the bacterial infection by the host’s immune system. PMID:28265270

  10. 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.

  11. 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.

  12. 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.

  13. 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.

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

    PubMed

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

    2016-07-07

    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.

  15. 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

  16. Neutrophilic myeloid-derived suppressor cells in cord blood modulate innate and adaptive immune responses

    PubMed Central

    Rieber, N; Gille, C; Köstlin, N; Schäfer, I; Spring, B; Ost, M; Spieles, H; Kugel, H A; Pfeiffer, M; Heininger, V; Alkhaled, M; Hector, A; Mays, L; Kormann, M; Zundel, S; Fuchs, J; Handgretinger, R; Poets, C F; Hartl, D

    2013-01-01

    Neonates show an impaired anti-microbial host defence, but the underlying immune mechanisms are not understood fully. Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell subset characterized by their capacity to suppress T cell immunity. In this study we demonstrate that a distinct MDSC subset with a neutrophilic/granulocytic phenotype (Gr-MDSCs) is highly increased in cord blood compared to peripheral blood of children and adults. Functionally, cord blood isolated Gr-MDSCs suppressed T cell proliferation efficiently as well as T helper type 1 (Th1), Th2 and Th17 cytokine secretion. Beyond T cells, cord blood Gr-MDSCs controlled natural killer (NK) cell cytotoxicity in a cell contact-dependent manner. These studies establish neutrophilic Gr-MDSCs as a novel immunosuppressive cell subset that controls innate (NK) and adaptive (T cell) immune responses in neonates. Increased MDSC activity in cord blood might serve as key fetomaternal immunosuppressive mechanism impairing neonatal host defence. Gr-MDSCs in cord blood might therefore represent a therapeutic target in neonatal infections. PMID:23701226

  17. Neutrophilic myeloid-derived suppressor cells in cord blood modulate innate and adaptive immune responses.

    PubMed

    Rieber, N; Gille, C; Köstlin, N; Schäfer, I; Spring, B; Ost, M; Spieles, H; Kugel, H A; Pfeiffer, M; Heininger, V; Alkhaled, M; Hector, A; Mays, L; Kormann, M; Zundel, S; Fuchs, J; Handgretinger, R; Poets, C F; Hartl, D

    2013-10-01

    Neonates show an impaired anti-microbial host defence, but the underlying immune mechanisms are not understood fully. Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell subset characterized by their capacity to suppress T cell immunity. In this study we demonstrate that a distinct MDSC subset with a neutrophilic/granulocytic phenotype (Gr-MDSCs) is highly increased in cord blood compared to peripheral blood of children and adults. Functionally, cord blood isolated Gr-MDSCs suppressed T cell proliferation efficiently as well as T helper type 1 (Th1), Th2 and Th17 cytokine secretion. Beyond T cells, cord blood Gr-MDSCs controlled natural killer (NK) cell cytotoxicity in a cell contact-dependent manner. These studies establish neutrophilic Gr-MDSCs as a novel immunosuppressive cell subset that controls innate (NK) and adaptive (T cell) immune responses in neonates. Increased MDSC activity in cord blood might serve as key fetomaternal immunosuppressive mechanism impairing neonatal host defence. Gr-MDSCs in cord blood might therefore represent a therapeutic target in neonatal infections.

  18. A bacteriophage encodes its own CRISPR/Cas adaptive response to evade host innate immunity.

    PubMed

    Seed, Kimberley D; Lazinski, David W; Calderwood, Stephen B; Camilli, Andrew

    2013-02-28

    Bacteriophages (or phages) are the most abundant biological entities on earth, and are estimated to outnumber their bacterial prey by tenfold. The constant threat of phage predation has led to the evolution of a broad range of bacterial immunity mechanisms that in turn result in the evolution of diverse phage immune evasion strategies, leading to a dynamic co-evolutionary arms race. Although bacterial innate immune mechanisms against phage abound, the only documented bacterial adaptive immune system is the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system, which provides sequence-specific protection from invading nucleic acids, including phage. Here we show a remarkable turn of events, in which a phage-encoded CRISPR/Cas system is used to counteract a phage inhibitory chromosomal island of the bacterial host. A successful lytic infection by the phage is dependent on sequence identity between CRISPR spacers and the target chromosomal island. In the absence of such targeting, the phage-encoded CRISPR/Cas system can acquire new spacers to evolve rapidly and ensure effective targeting of the chromosomal island to restore phage replication.

  19. Crosstalk between innate and adaptive immunity in hepatitis B virus infection.

    PubMed

    Wang, Li; Wang, Kai; Zou, Zhi-Qiang

    2015-12-28

    Hepatitis B virus (HBV) infection is a major public health problem worldwide. HBV is not directly cytotoxic to infected hepatocytes; the clinical outcome of infection results from complicated interactions between the virus and the host immune system. In acute HBV infection, initiation of a broad, vigorous immune response is responsible for viral clearance and self-limited inflammatory liver disease. Effective and coordinated innate and adaptive immune responses are critical for viral clearance and the development of long-lasting immunity. Chronic hepatitis B patients fail to mount efficient innate and adaptive immune responses to the virus. In particular, HBV-specific cytotoxic T cells, which are crucial for HBV clearance, are hyporesponsiveness to HBV infection. Accumulating experimental evidence obtained from the development of animal and cell line models has highlighted the importance of innate immunity in the early control of HBV spread. The virus has evolved immune escape strategies, with higher HBV loads and HBV protein concentrations associated with increasing impairment of immune function. Therefore, treatment of HBV infection requires inhibition of HBV replication and protein expression to restore the suppressed host immunity. Complicated interactions exist not only between innate and adaptive responses, but also among innate immune cells and different components of adaptive responses. Improved insight into these complex interactions are important in designing new therapeutic strategies for the treatment HBV infection. In this review, we summarize the current knowledge regarding the cross-talk between the innate and adaptive immune responses and among different immunocytes in HBV infection.

  20. Crosstalk between innate and adaptive immunity in hepatitis B virus infection

    PubMed Central

    Wang, Li; Wang, Kai; Zou, Zhi-Qiang

    2015-01-01

    Hepatitis B virus (HBV) infection is a major public health problem worldwide. HBV is not directly cytotoxic to infected hepatocytes; the clinical outcome of infection results from complicated interactions between the virus and the host immune system. In acute HBV infection, initiation of a broad, vigorous immune response is responsible for viral clearance and self-limited inflammatory liver disease. Effective and coordinated innate and adaptive immune responses are critical for viral clearance and the development of long-lasting immunity. Chronic hepatitis B patients fail to mount efficient innate and adaptive immune responses to the virus. In particular, HBV-specific cytotoxic T cells, which are crucial for HBV clearance, are hyporesponsiveness to HBV infection. Accumulating experimental evidence obtained from the development of animal and cell line models has highlighted the importance of innate immunity in the early control of HBV spread. The virus has evolved immune escape strategies, with higher HBV loads and HBV protein concentrations associated with increasing impairment of immune function. Therefore, treatment of HBV infection requires inhibition of HBV replication and protein expression to restore the suppressed host immunity. Complicated interactions exist not only between innate and adaptive responses, but also among innate immune cells and different components of adaptive responses. Improved insight into these complex interactions are important in designing new therapeutic strategies for the treatment HBV infection. In this review, we summarize the current knowledge regarding the cross-talk between the innate and adaptive immune responses and among different immunocytes in HBV infection. PMID:26730277

  1. Oxidation matters: the ubiquitin proteasome system connects innate immune mechanisms with MHC class I antigen presentation.

    PubMed

    Warnatsch, Annika; Bergann, Theresa; Krüger, Elke

    2013-09-01

    During innate immune responses the delicate balance of protein synthesis, quality control and degradation is severely challenged by production of radicals and/or the massive synthesis of pathogen proteins. The regulated degradation of ubiquitin-tagged proteins by the ubiquitin proteasome system (UPS) represents one major pathway for the maintenance of cellular proteostasis and regulatory processes under these conditions. In addition, MHC class I antigen presentation is strictly dependent on an appropriate peptide supply by the UPS to efficiently prime CD8(+) T cells and to initiate an adaptive immune response. We here discuss recent efforts in defining the link between innate immune mechanisms like cytokine and ROS production, the induction of an efficient adaptive immune response and the specific involvement of the UPS therein. Cytokines and/or infections induce translation and the production of free radicals, which in turn confer oxidative damage to nascent as well as folded proteins. In parallel, the same signaling cascades are able to accelerate the protein turnover by the concomitantly induced ubiquitin conjugation and degradation of such damaged polypeptides by immunoproteasomes. The ability of immunoproteasomes to efficiently degrade such oxidant-damaged ubiquitylated proteins protects cells from accumulating toxic ubiquitin-rich aggregates. At the same time, this innate immune mechanism facilitates a sufficient peptide supply for MHC class I antigen presentation and connects it to initiation of adaptive immunity.

  2. Evolution of Cell-Autonomous Effector Mechanisms in Macrophages versus Non-Immune Cells

    PubMed Central

    Gaudet, Ryan G.; Bradfield, Clinton J.; MacMicking, John D.

    2016-01-01

    Summary Specialized adaptations for killing microbes is synonymous with phagocytic cells including macrophages, monocytes, inflammatory neutrophils and eosinophils. Recent genome sequencing of extant species, however, reveals analogous antimicrobial machineries exist in certain non-immune cells and also within species that ostensibly lack a well-defined immune system. Here we probe the evolutionary record for clues about the ancient and diverse phylogenetic origins of macrophage killing mechanisms and how some of their properties are shared with cells outside the traditional bounds of immunity in higher vertebrates such as mammals. PMID:28087931

  3. The Memories of NK Cells: Innate-Adaptive Immune Intrinsic Crosstalk

    PubMed Central

    Ortolani, Claudio; del Zotto, Genny; Luchetti, Francesca; Canonico, Barbara; Artico, Marco; Papa, Stefano

    2016-01-01

    Although NK cells are considered part of the innate immune system, a series of evidences has demonstrated that they possess characteristics typical of the adaptive immune system. These NK adaptive features, in particular their memory-like functions, are discussed from an ontogenetic and evolutionary point of view. PMID:28078307

  4. No evidence of local adaptation of immune responses to Gyrodactylus in three-spined stickleback (Gasterosteus aculeatus).

    PubMed

    Robertson, Shaun; Bradley, Janette E; MacColl, Andrew D C

    2017-01-01

    Parasitism represents one of the most widespread lifestyles in the animal kingdom, with the potential to drive coevolutionary dynamics with their host population. Where hosts and parasites evolve together, we may find local adaptation. As one of the main host defences against infection, there is the potential for the immune response to be adapted to local parasites. In this study, we used the three-spined stickleback and its Gyrodactylus parasites to examine the extent of local adaptation of parasite infection dynamics and the immune response to infection. We took two geographically isolated host populations infected with two distinct Gyrodactylus species and performed a reciprocal cross-infection experiment in controlled laboratory conditions. Parasite burdens were monitored over the course of the infection, and individuals were sampled at multiple time points for immune gene expression analysis. We found large differences in virulence between parasite species, irrespective of host, and maladaptation of parasites to their sympatric host. The immune system responded to infection, with a decrease in expression of innate and Th1-type adaptive response genes in fish infected with the less virulent parasite, representing a marker of a possible resistance mechanism. There was no evidence of local adaptation in immune gene expression levels. Our results add to the growing understanding of the extent of host-parasite local adaptation, and demonstrate a systemic immune response during infection with a common ectoparasite. Further immunological studies using the stickleback-Gyrodactylus system can continue to contribute to our understanding of the function of the immune response in natural populations.

  5. 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

  6. Loss of adaptive mechanisms during aging.

    PubMed

    Adelman, R C

    1979-05-01

    Factors contributing to modifications in the capability for enzyme adaptation as an expression of aging are reviewed. Specific examples of altered enzyme adaptations during aging include the responses of hepatic glucokinase activity to glucose and hepatic tyrosine aminotransferase activity to starvation in Sprague-Dawley rats. These impaired enzyme adaptations apparently are not the consequence of alterations in hepatic function during aging. Instead, they reflect disturbances in extrahepatic hormonal regulatory mechanisms. Specific examples include modifications in the control of circulating levels of insulin glucagon, corticosteroids, and thyroid hormones. Age-dependent changes in the regulation of circulating levels of insulin probably originate within the impaired ability of pancreatic islets of Langerhans to secrete the hormone in response to glucose. The rationale for exploiting this experimental approach as a means to understand biological aging is discussed.

  7. 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.

  8. Modulation of dendritic cell innate and adaptive immune functions by oral and sublingual immunotherapy.

    PubMed

    Frischmeyer-Guerrerio, Pamela A; Keet, Corinne A; Guerrerio, Anthony L; Chichester, Kristin L; Bieneman, Anja P; Hamilton, Robert G; Wood, Robert A; Schroeder, John T

    2014-11-01

    Sublingual (SLIT) and oral immunotherapy (OIT) are promising treatments for food allergy, but underlying mechanisms are poorly understood. Dendritic cells (DCs) induce and maintain Th2-type allergen-specific T cells, and also regulate innate immunity through their expression of Toll-like receptors (TLRs). We examined how SLIT and OIT influenced DC innate and adaptive immune responses in children with IgE-mediated cow's milk (CM) allergy. SLIT, but not OIT, decreased TLR-induced IL-6 secretion by myeloid DCs (mDCs). SLIT and OIT altered mDC IL-10 secretion, a potent inhibitor of FcεRI-dependent pro-inflammatory responses. OIT uniquely augmented IFN-α and decreased IL-6 secretion by plasmacytoid DCs (pDCs), which was associated with reduced TLR-induced IL-13 release in pDC-T cell co-cultures. Both SLIT and OIT decreased Th2 cytokine secretion to CM in pDC-T, but not mDC-T, co-cultures. Therefore, SLIT and OIT exert unique effects on DC-driven innate and adaptive immune responses, which may inhibit allergic inflammation and promote tolerance.

  9. Aging and Immune Function: Molecular Mechanisms to Interventions

    PubMed Central

    Ponnappan, Subramaniam

    2011-01-01

    Abstract The immune system of an organism is an essential component of the defense mechanism aimed at combating pathogenic stress. Age-associated immune dysfunction, also dubbed “immune senescence,” manifests as increased susceptibility to infections, increased onset and progression of autoimmune diseases, and onset of neoplasia. Over the years, extensive research has generated consensus in terms of the phenotypic and functional defects within the immune system in various organisms, including humans. Indeed, age-associated alterations such as thymic involution, T cell repertoire skewing, decreased ability to activate naïve T cells and to generate robust memory responses, have been shown to have a causative role in immune decline. Further, understanding the molecular mechanisms underlying the generation of proteotoxic stress, DNA damage response, modulation of ubiquitin proteasome pathway, and regulation of transcription factor NFκB activation, in immune decline, have paved the way to delineating signaling pathways that cross-talk and impact immune senescence. Given the role of the immune system in combating infections, its effectiveness with age may well be a marker of health and a predictor of longevity. It is therefore believed that a better understanding of the mechanisms underlying immune senescence will lead to an effective interventional strategy aimed at improving the health span of individuals. Antioxid. Redox Signal. 14, 1551–1585. PMID:20812785

  10. The role of tissue adaptation and graft size in immune tolerance.

    PubMed

    Hauben, Ehud; Roncarolo, Maria Grazia; Draghici, Elena; Nevo, Uri

    2007-11-01

    Understanding how immune tolerance is induced and maintained is critical for our approach to immune-related diseases. Ecoimmunity is a new theory that views the immune system-tissue interaction as a co-adapting predator-prey system. Ecoimmunity suggests that tissues adapt to the selective immune pressure during ontogeny and throughout life. Therefore, immune tolerance towards 'self' represents a symmetric balance between the propensity of the immune system to prey on 'self' cells, and the tissue's specific capacity to undergo phenotypic adaptations in order to avoid destructive immune interaction. According to this theory, we hypothesized that tissues of adult immune-deficient mice, which are not exposed to selective immune pressure, will not withstand immune activity and will therefore display higher susceptibility to graft rejection. To test this prediction, C57Bl/6 wild type female mice were rendered diabetic by streptozotocin and transplanted with syngeneic pancreatic islets isolated from either immune-deficient C57Bl/6 SCID or wild type females. Remarkably, recipients of islet grafts from immune-deficient syngeneic donors displayed significantly impaired glucose homeostasis compared to mice transplanted with islets of wild type donors (p<0.001, two way repeated measures ANOVA). The severity of this impairment was correlated with islet graft size, suggesting a capacity of transplanted islets to gradually acquire a tolerogenic phenotype. These findings support the view of graft survival that is based on 'natural selection' of tissue cells. In addition, we describe a new experimental system for molecular characterization of self-tolerance.

  11. Immune system - part I. Fundamentals of innate immunity with emphasis on molecular and cellular mechanisms of inflammatory response.

    PubMed

    Cruvinel, Wilson de Melo; Mesquita, Danilo; Araújo, Júlio Antônio Pereira; Catelan, Tânia Tieko Takao; de Souza, Alexandre Wagner Silva; da Silva, Neusa Pereira; Andrade, Luís Eduardo Coelho

    2010-01-01

    The immune system consists of an intricate network of organs, cells, and molecules responsible for maintaining the body's homeostasis and responding to aggression in general. Innate immunity operates in conjunction with adaptive immunity and is characterized by rapid response to aggression, regardless of previous stimulus, being the organism first line of defense. Its mechanisms include physical, chemical and biological barriers, cellular components, as well as soluble molecules. The organism first line of defense against tissue damage involves several steps closely integrated and constituted by different components of this system. The aim of this review is to restore the foundations of this response, which has high complexity and consists of several components that converge to articulate the development of adaptive immune response. We selected some of the following steps to review: perception and molecular recognition of aggressive agents; activation of intracellular pathways, which result in vascular and tissue changes; production of a myriad of mediators with local and systemic effects on cell activation and proliferation, synthesis of new products involved in the chemoattraction and migration of cells specialized in destruction and removal of offending agent; and finally, tissue recovery with restoration of functional tissue or organ.

  12. The role of adaptive immunity as an ecological filter on the gut microbiota in zebrafish.

    PubMed

    Stagaman, Keaton; Burns, Adam R; Guillemin, Karen; Bohannan, Brendan Jm

    2017-03-17

    All animals live in intimate association with communities of microbes, collectively referred to as their microbiota. Certain host traits can influence which microbial taxa comprise the microbiota. One potentially important trait in vertebrate animals is the adaptive immune system, which has been hypothesized to act as an ecological filter, promoting the presence of some microbial taxa over others. Here we surveyed the intestinal microbiota of 68 wild-type zebrafish, with functional adaptive immunity, and 61 rag1(-) zebrafish, lacking functional B- and T-cell receptors, to test the role of adaptive immunity as an ecological filter on the intestinal microbiota. In addition, we tested the robustness of adaptive immunity's filtering effects to host-host interaction by comparing the microbiota of fish populations segregated by genotype to those containing both genotypes. The presence of adaptive immunity individualized the gut microbiota and decreased the contributions of neutral processes to gut microbiota assembly. Although mixing genotypes led to increased phylogenetic diversity in each, there was no significant effect of adaptive immunity on gut microbiota composition in either housing condition. Interestingly, the most robust effect on microbiota composition was co-housing within a tank. In all, these results suggest that adaptive immunity has a role as an ecological filter of the zebrafish gut microbiota, but it can be overwhelmed by other factors, including transmission of microbes among hosts.The ISME Journal advance online publication, 17 March 2017; doi:10.1038/ismej.2017.28.

  13. [Mechanisms of immune system contribution to efficiency of antitumor cytostatic therapy].

    PubMed

    Stakheeva, M N; Kzhyshkowska, Yu G; Buldakov, M A; Cherdyntseva, N V

    2015-01-01

    Increasing the efficiency of antitumor therapy is one of major relevant tasks of oncology today. During recent years experimental evidence for active involvement of immune system in the regulation antitumor effects of cytostatic thereby has been obtained and theoretically justified. It was demonstrated that efficient cytostatic treatment is related to the cytotoxic activities of immune cells targeted against tumor cells. Such cytotoxic activities of immune cells are induced by radiotherapy or chemotherapy, where both innate and adaptive immune mechanisms are involved. However the disturbance in the functions of immune system can result in the impaired efficiency of cytostatic anti-tumor therapy. Cytotoxic agents can affect immune reactions by increasing the antigenic properties of tumor cells, facilitating their recognition of immune system, by stimulation of functional activation effector immune cells, elimination of immunosuppressive factors as well as systemic effects of antitumor therapy. A consideration of the crucial role of immune system in the providing of the efficiency of cytostatic antitumor therapy develops novel therapeutic approaches for treatment of malignant disorders based on balanced synergistic action of cytostatic agents and innovative immunomodulatory approaches.

  14. Chronic joint disease caused by persistent Chikungunya virus infection is controlled by the adaptive immune response.

    PubMed

    Hawman, David W; Stoermer, Kristina A; Montgomery, Stephanie A; Pal, Pankaj; Oko, Lauren; Diamond, Michael S; Morrison, Thomas E

    2013-12-01

    Chikungunya virus (CHIKV) is a reemerging mosquito-borne pathogen that causes incapacitating disease in humans characterized by intense joint pain that can persist for weeks, months, or even years. Although there is some evidence of persistent CHIKV infection in humans suffering from chronic rheumatologic disease symptoms, little is known about chronic disease pathogenesis, and no specific therapies exist for acute or chronic CHIKV disease. To investigate mechanisms of chronic CHIKV-induced disease, we utilized a mouse model and defined the duration of CHIKV infection in tissues and the associated histopathological changes. Although CHIKV RNA was readily detectable in a variety of tissues very early after infection, CHIKV RNA persisted specifically in joint-associated tissues for at least 16 weeks. Inoculation of Rag1(-/-) mice, which lack T and B cells, resulted in higher viral levels in a variety of tissues, suggesting that adaptive immunity controls the tissue specificity and persistence of CHIKV infection. The presence of CHIKV RNA in tissues of wild-type and Rag1(-/-) mice was associated with histopathological evidence of synovitis, arthritis, and tendonitis; thus, CHIKV-induced persistent arthritis is not mediated primarily by adaptive immune responses. Finally, we show that prophylactic administration of CHIKV-specific monoclonal antibodies prevented the establishment of CHIKV persistence, whereas therapeutic administration had tissue-specific efficacy. These findings suggest that chronic musculoskeletal tissue pathology is caused by persistent CHIKV infection and controlled by adaptive immune responses. Our results have significant implications for the development of strategies to mitigate the disease burden associated with CHIKV infection in humans.

  15. Mice lacking components of adaptive immunity show increased Brucella abortus virB mutant colonization.

    PubMed

    Rolán, Hortensia García; Tsolis, Renée M

    2007-06-01

    The Brucella abortus type IV secretion system (T4SS), encoded by the virB genes, is essential for survival in mononuclear phagocytes in vitro. In the mouse model, a B. abortus virB mutant was initially able to colonize the spleen at the level of the wild type for approximately 3 to 5 days, which coincided with the development of adaptive immunity. To investigate the relationship between survival in macrophages cultivated in vitro and persistence in tissues in vivo, we tested the ability of mutant mice lacking components of adaptive immunity to eliminate the virB mutant from the spleen during a mixed infection with the B. abortus wild type. Ifng(-/-) or beta(2)m(-/-) mice were able to clear the virB mutant to the same degree as control mice. However, spleens of Rag1(-/-) mice and Igh6(-/-) mice were more highly colonized by the virB mutant than control mice after 14 to 21 days, suggesting that, in these mice, there is not an absolute requirement for the T4SS to mediate persistence of B. abortus in the spleen. Macrophages isolated from Igh6(-/-) mice killed the virB mutant to the same extent as macrophages from control mice, showing that the reduced ability of these mice to clear the virB mutant from the spleen does not correlate with diminished macrophage function in vitro. These results show that in the murine model host, the T4SS is required for persistence beyond 3 to 5 days after infection and suggest that the T4SS may contribute to evasion of adaptive immune mechanisms by B. abortus.

  16. Mechanisms of protective immunity in Hymenolepis nana/mouse model.

    PubMed

    Bortoletti, G; Gabriele, F; Palmas, C

    1992-12-01

    Some immunological and parasitological aspects related to the infection of Hymenolepsis nana in mice are summarized in this review, focusing on the immune effector mechanisms involved in this host/parasite relationship. H. nana is a small cestode tapeworm of man and mice. A primary egg-infection determines within few days a strong immunity. Immunity elicited by low-level primary infection is effective as a high-level infection. The protective role of both humoral and cell-mediated immunity is summarized. The histological findings demonstrate that eosinophils and mast-cells are implicated as effector cells. This review is an attempt to re-examine, at low-level infection, the immune mechanisms in H. nana/mouse model.

  17. 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.

  18. Innate and adaptive immune cells in the tumor microenvironment

    PubMed Central

    Gajewski, Thomas F; Schreiber, Hans; Fu, Yang-Xin

    2014-01-01

    Most tumor cells express antigens that can mediate recognition by host CD8+ T cells. Cancers that are detected clinically must have evaded antitumor immune responses to grow progressively. Recent work has suggested two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment. One major subset shows a T cell–inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These tumors appear to resist immune attack through the dominant inhibitory effects of immune system–suppressive pathways. The other major phenotype lacks this T cell–inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect. PMID:24048123

  19. Immune mechanisms linked to depression via oxidative stress and neuroprogression.

    PubMed

    Bakunina, Nataliia; Pariante, Carmine M; Zunszain, Patricia A

    2015-01-10

    Emerging evidence suggests the significant role of inflammation and oxidative stress as main contributors to the neuroprogression that is observed in major depressive disorder (MDD), where patients show increased inflammatory and oxidative stress biomarkers. The process of neuroprogression includes stage-related neurodegeneration, cell death, reduced neurogenesis, reduced neuronal plasticity and increased autoimmune responses. Oxidative stress is a consequence of the biological imbalance between Reactive Oxygen Species (ROS) and antioxidants, leading to the alteration of biomolecules and the loss of control of the intracellular redox-related signaling pathways. ROS serve as crucial secondary messengers in signal transduction and significantly affect inflammatory pathways by activating NF-κB and MAPK family stress kinases. When present in excess, ROS inflict damage, affecting cellular constituents with the formation of pro-inflammatory molecules, such as malondialdehyde, 4-Hydroxynonenal, neoepitopes and damage-associated molecular patterns promoting immune response, and ultimately leading to cell death. The failure of cells to adapt to the changes in redox homeostasis and the subsequent cell death, together with the damage caused by inflammatory mediators, have been considered as major causes of neuroprogression and hence MDD. Both an activated immune-inflammatory system and increased oxidative stress act synergistically, complicating our understanding of the pathogenesis of depression. The cascade of antioxidative and inflammatory events is orchestrated by several transcription factors, with Nrf2 and NF-κB having particular relevance to MDD. This review focuses on potential molecular mechanisms through which impaired redox homeostasis and neuroinflammation can affect the neuronal environment and contribute to depression This article is protected by copyright. All rights reserved.

  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. HHX-5, a derivative of sesquiterpene from Chinese agarwood, suppresses innate and adaptive immunity via inhibiting STAT signaling pathways.

    PubMed

    Zhu, Zhixiang; Zhao, Yunfang; Huo, Huixia; Gao, Xiaoli; Zheng, Jiao; Li, Jun; Tu, Pengfei

    2016-11-15

    Induction of excessive, prolonged, or dysregulated immune responses causes immunological disorders, such as inflammatory diseases, autoimmune diseases, allergic diseases, and organ-graft rejections. In the present study, we investigated the inhibitory effects of HHX-5, a derivative of sesquiterpene from Chinese agarwood, on innate and adaptive immunity for revealing its potential to treat above immunological disorders. The results showed that HHX-5 significantly inhibited the activation of macrophages and neutrophils which play important roles in innate immunity. Furthermore, HHX-5 strongly suppressed adaptive immunity via inhibiting differentiation of naive CD4(+) T cells into Th1, Th2, and Th17 cells and suppressing activation, proliferation and differentiation of CD8(+) T cells and B cells. The mechanism study showed that HHX-5 significantly inhibited STAT1 signaling pathway in macrophages and suppressed STAT1, STAT4, STAT5, and STAT6 signaling pathways in naive CD4(+) T cells. In conclusion, we demonstrated that HHX-5 can strongly inhibit innate and adaptive immunity via suppressing STAT signaling pathways and has potential to be developed into therapeutic drug for treat immunological disorders.

  2. [Insulin resistance as a mechanism of adaptation during human evolution].

    PubMed

    Ricart, W; Fernández-Real, J M

    2010-10-01

    The recent application of concepts of evolution to human disease is proving useful to understand certain pathophysiological mechanisms of different entities that span genomic alterations of immunity, respiratory and hormone function, and the circulatory and neural systems. However, effort has concentrated on explaining the keys to adaptation that define human metabolism and, since the early 1960s, several theories have been developed. This article reviews some of the hypotheses postulated in recent years on the potential benefit of insulin resistance and discusses the most recent knowledge. The concept of the thrifty gene seems to have been definitively refuted by current knowledge. The current paradigm describes an interaction between the metabolic and the immune systems resulting from their coevolution, promoted by evolutionary pressures triggered by fasting, infection and intake of different foods. The activation and regulation of these ancient mechanisms in integrated and interdependent areas defines insulin resistance as a survival strategy that is critical during fasting and in the fight against infection. The relationship with some components of the diet and, particularly, with the symbiotic intestinal microflora points to new paradigms in understanding the pathophysiology of obesity, metabolic syndrome and type 2 diabetes mellitus.

  3. Immune and genetic mechanisms in COPD: possible targets for therapeutic interventions.

    PubMed

    Tzortzaki, Eleni G; Papi, Alberto; Neofytou, Eirini; Soulitzis, Nikolaos; Siafakas, Nikolaos M

    2013-02-01

    Genetic, immune and environmental interactions are key elements for the development of COPD. Cigarette smoking is considered the primary risk factor initiating inflammatory cascades in genetically susceptible individuals. The "danger signals" elicited by the injured cells of non-specific immunity induce the downstream activation of proinflammatory cascades and antigen-specific adaptive immune responses. The produced oxidative stress further damages the lung leading to acquired genetic changes (histone deacetylation, microsatellite DNA instability, DNA methylation, telomere shortening, miRNA alterations) due to an inefficient DNA repair machinery. On the other hand, augmented apoptosis, impaired efferocytosis and abnormal tissue remodeling contribute to the chronic inflammatory response and tissue destruction in COPD. This review focuses on the role of genetic, epigenetic and immune mechanisms in the development of COPD in order to put forward possible prognostic and therapeutic targets.

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

    PubMed

    Hansen, Thomas R; Smirnova, Natalia P; Webb, Brett T; Bielefeldt-Ohmann, Helle; Sacco, Randy E; Van Campen, Hana

    2015-06-01

    Infection of pregnant cows with noncytopathic (ncp) bovine viral diarrhea virus (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 infection with ncpBVDV in the fetus has been attributed to the inability to mount an immune response before 90-150 days of gestational age. The result is 'immune tolerance', persistent viral replication and shedding of ncpBVDV. In contrast, we describe the chronic upregulation of fetal Type I interferon (IFN) pathway genes and the induction of IFN-γ pathways in fetuses of cows infected on day 75 of gestation. Persistently infected (PI) fetal IFN-γ concentrations also increased at day 97 at the peak of fetal viremia and IFN-γ mRNA was significantly elevated in fetal thymus, liver and spleen 14-22 days post maternal inoculation. PI fetuses respond to ncpBVDV infection through induction of Type I IFN and IFN-γ activated genes leading to a reduction in ncpBVDV titer. We hypothesize that fetal infection with BVDV persists because of impaired induction of IFN-γ in the face of activated Type I IFN responses. Clarification of the mechanisms involved in the IFN-associated pathways during BVDV fetal infection may lead to better detection methods, antiviral compounds and selection of genetically resistant breeding animals.

  5. Mesenchymal Stem Cells Regulate the Innate and Adaptive Immune Responses Dampening Arthritis Progression

    PubMed Central

    Contreras, R. A.; Djouad, F.

    2016-01-01

    Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to immunomodulate cells from both the innate and the adaptive immune systems promoting an anti-inflammatory environment. During the last decade, MSCs have been intensively studied in vitro and in vivo in experimental animal model of autoimmune and inflammatory disorders. Based on these studies, MSCs are currently widely used for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) characterized by complex deregulation of the immune systems. However, the therapeutic properties of MSCs in arthritis are still controverted. These controversies might be due to the diversity of MSC sources and isolation protocols used, the time, the route and dose of MSC administration, the variety of the mechanisms involved in the MSCs suppressive effects, and the complexity of arthritis pathogenesis. In this review, we discuss the role of the interactions between MSCs and the different immune cells associated with arthritis pathogenesis and the possible means described in the literature that could enhance MSCs therapeutic potential counteracting arthritis development and progression. PMID:27847522

  6. Mesenchymal Stem Cells Regulate the Innate and Adaptive Immune Responses Dampening Arthritis Progression.

    PubMed

    Contreras, R A; Figueroa, F E; Djouad, F; Luz-Crawford, P

    2016-01-01

    Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to immunomodulate cells from both the innate and the adaptive immune systems promoting an anti-inflammatory environment. During the last decade, MSCs have been intensively studied in vitro and in vivo in experimental animal model of autoimmune and inflammatory disorders. Based on these studies, MSCs are currently widely used for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) characterized by complex deregulation of the immune systems. However, the therapeutic properties of MSCs in arthritis are still controverted. These controversies might be due to the diversity of MSC sources and isolation protocols used, the time, the route and dose of MSC administration, the variety of the mechanisms involved in the MSCs suppressive effects, and the complexity of arthritis pathogenesis. In this review, we discuss the role of the interactions between MSCs and the different immune cells associated with arthritis pathogenesis and the possible means described in the literature that could enhance MSCs therapeutic potential counteracting arthritis development and progression.

  7. Mechanisms of adaptation in the intestinal parasite Giardia lamblia.

    PubMed

    Lujan, Hugo D

    2011-01-01

    Giardia lamblia, a parasite of humans, is a major source of waterborne diarrhoeal disease. Giardia is also an excellent system to study basic biochemical processes because it is a single-celled eukaryote with a small genome and its entire life cycle can be replicated in vitro. Giardia trophozoites undergo fundamental changes to survive outside the intestine of their host by differentiating into infective cysts. Encystation entails the synthesis, processing, transport, secretion and extracellular assembly of cyst wall components. To survive within the intestine, Giardia undergoes antigenic variation, a process by which the parasite continuously switches its major surface molecules, allowing the parasite to evade the host's immune response and produce chronic and recurrent infections. The objective of the present chapter is to provide a better understanding of the molecular mechanisms involved in adaptation and differentiation in Giardia, with a particular focus on the process of encystation and antigenic variation of this interesting micro-organism.

  8. Metabolic mechanisms of cancer-induced inhibition of immune responses.

    PubMed

    Viola, Antonella; Bronte, Vincenzo

    2007-08-01

    During progression, tumors become refractory to the offensive weapons of the immune system. It has been known for a long time that the tumor microenvironment presents a profound modification in the metabolism of arachidonic acid and amino acids such as l-triptophan and l-arginine. However, only in the last decade we have started to appreciate how these changes might cause dysfunctions in cells of both adaptive and innate immune system. The knowledge of these complex and partially interconnected metabolic pathways is offering new targets for an integrated pharmacological approach aiming at freeing tumor-specific T lymphocytes from the latches of cancer influence.

  9. The immunomodulatory role of the hypothalamus-pituitary-gonad axis: Proximate mechanism for reproduction-immune trade offs?

    PubMed

    Segner, Helmut; Verburg-van Kemenade, B M Lidy; Chadzinska, Magdalena

    2017-01-01

    The present review discusses the communication between the hypothalamic-pituitary-gonad (HPG) axis and the immune system of vertebrates, attempting to situate the HPG-immune interaction into the context of life history trade-offs between reproductive and immune functions. More specifically, (i) we review molecular and cellular interactions between hormones of the HPG axis, and, as far as known, the involved mechanisms on immune functions, (ii) we evaluate whether the HPG-immune crosstalk serves as proximate mechanism mediating reproductive-immune trade-offs, and (iii) we ask whether the nature of the HPG-immune interaction is conserved throughout vertebrate evolution, despite the changes in immune functions, reproductive modes, and life histories. In all vertebrate classes studied so far, HPG hormones have immunomodulatory functions, and indications exist that they contribute to reproduction-immunity resource trade-offs, although the very limited information available for most non-mammalian vertebrates makes it difficult to judge how comparable or different the interactions are. There is good evidence that the HPG-immune crosstalk is part of the proximate mechanisms underlying the reproductive-immune trade-offs of vertebrates, but it is only one factor in a complex network of factors and processes. The fact that the HPG-immune interaction is flexible and can adapt to the functional and physiological requirements of specific life histories. Moreover, the assumption of a relatively fixed pattern of HPG influence on immune functions, with, for example, androgens always leading to immunosuppression and estrogens always being immunoprotective, is probably oversimplified, but the HPG-immune interaction can vary depending on the physiological and envoironmental context. Finally, the HPG-immune interaction is not only driven by resource trade-offs, but additional factors such as, for instance, the evolution of viviparity shape this neuroendocrine-immune relationship.

  10. Mechanisms of Sensorimotor Adaptation to Centrifugation

    NASA Technical Reports Server (NTRS)

    Paloski, W. H.; Wood, S. J.; Kaufman, G. D.

    1999-01-01

    We postulate that centripetal acceleration induced by centrifugation can be used as an inflight sensorimotor countermeasure to retain and/or promote appropriate crewmember responses to sustained changes in gravito-inertial force conditions. Active voluntary motion is required to promote vestibular system conditioning, and both visual and graviceptor sensory feedback are critical for evaluating internal representations of spatial orientation. The goal of our investigation is to use centrifugation to develop an analog to the conflicting visual/gravito-inertial force environment experienced during space flight, and to use voluntary head movements during centrifugation to study mechanisms of adaptation to altered gravity environments. We address the following two hypotheses: (1) Discordant canal-otolith feedback during head movements in a hypergravity tilted environment will cause a reorganization of the spatial processing required for multisensory integration and motor control, resulting in decreased postural stability upon return to normal gravity environment. (2) Adaptation to this "gravito-inertial tilt distortion" will result in a negative after-effect, and readaptation will be expressed by return of postural stability to baseline conditions. During the third year of our grant we concentrated on examining changes in balance control following 90-180 min of centrifugation at 1.4 9. We also began a control study in which we exposed subjects to 90 min of sustained roll tilt in a static (non-rotating) chair. This allowed us to examine adaptation to roll tilt without the hypergravity induced by centrifugation. To these ends, we addressed the question: Is gravity an internal calibration reference for postural control? The remainder of this report is limited to presenting preliminary findings from this study.

  11. 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.

  12. [Immune mechanisms in the development of hemorrhagic stroke].

    PubMed

    Sapin, M R; Sergeeva, S P; Erofeeva, L M; Koplik, E V

    2008-01-01

    The role played by immune mechanisms in intracerebral hemorrhage (ICH) was evaluated based on the studies of thymus structure and cell composition in rats showing different degree of tolerance to emotional stress. A new experimental ICH model is proposed. It is concluded that both stereotype and autoimmune mechanisms are involved in the development of ICH.

  13. Phenotypic plasticity: molecular mechanisms and adaptive significance.

    PubMed

    Kelly, Scott A; Panhuis, Tami M; Stoehr, Andrew M

    2012-04-01

    Phenotypic plasticity can be broadly defined as the ability of one genotype to produce more than one phenotype when exposed to different environments, as the modification of developmental events by the environment, or as the ability of an individual organism to alter its phenotype in response to changes in environmental conditions. Not surprisingly, the study of phenotypic plasticity is innately interdisciplinary and encompasses aspects of behavior, development, ecology, evolution, genetics, genomics, and multiple physiological systems at various levels of biological organization. From an ecological and evolutionary perspective, phenotypic plasticity may be a powerful means of adaptation and dramatic examples of phenotypic plasticity include predator avoidance, insect wing polymorphisms, the timing of metamorphosis in amphibians, osmoregulation in fishes, and alternative reproductive tactics in male vertebrates. From a human health perspective, documented examples of plasticity most commonly include the results of exercise, training, and/or dieting on human morphology and physiology. Regardless of the discipline, phenotypic plasticity has increasingly become the target of a plethora of investigations with the methodological approaches utilized ranging from the molecular to whole organsimal. In this article, we provide a brief historical outlook on phenotypic plasticity; examine its potential adaptive significance; emphasize recent molecular approaches that provide novel insight into underlying mechanisms, and highlight examples in fishes and insects. Finally, we highlight examples of phenotypic plasticity from a human health perspective and underscore the use of mouse models as a powerful tool in understanding the genetic architecture of phenotypic plasticity.

  14. Prophylactic and therapeutic modulation of innate and adaptive immunity against mucosal infection of herpes simplex virus.

    PubMed

    Uyangaa, Erdenebileg; Patil, Ajit Mahadev; Eo, Seong Kug

    2014-08-01

    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.

  15. 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

  16. Adaptive mechanically controlled lubrication mechanism found in articular joints.

    PubMed

    Greene, George W; Banquy, Xavier; Lee, Dong Woog; Lowrey, Daniel D; Yu, Jing; Israelachvili, Jacob N

    2011-03-29

    Articular cartilage is a highly efficacious water-based tribological system that is optimized to provide low friction and wear protection at both low and high loads (pressures) and sliding velocities that must last over a lifetime. Although many different lubrication mechanisms have been proposed, it is becoming increasingly apparent that the tribological performance of cartilage cannot be attributed to a single mechanism acting alone but on the synergistic action of multiple "modes" of lubrication that are adapted to provide optimum lubrication as the normal loads, shear stresses, and rates change. Hyaluronic acid (HA) is abundant in cartilage and synovial fluid and widely thought to play a principal role in joint lubrication although this role remains unclear. HA is also known to complex readily with the glycoprotein lubricin (LUB) to form a cross-linked network that has also been shown to be critical to the wear prevention mechanism of joints. Friction experiments on porcine cartilage using the surface forces apparatus, and enzymatic digestion, reveal an "adaptive" role for an HA-LUB complex whereby, under compression, nominally free HA diffusing out of the cartilage becomes mechanically, i.e., physically, trapped at the interface by the increasingly constricted collagen pore network. The mechanically trapped HA-LUB complex now acts as an effective (chemically bound) "boundary lubricant"--reducing the friction force slightly but, more importantly, eliminating wear damage to the rubbing/shearing surfaces. This paper focuses on the contribution of HA in cartilage lubrication; however, the system as a whole requires both HA and LUB to function optimally under all conditions.

  17. The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance.

    PubMed

    Winer, Shawn; Winer, Daniel A

    2012-09-01

    Over the past decade, chronic inflammation in visceral adipose tissue (VAT) has gained acceptance as a lead promoter of insulin resistance in obesity. A great deal of evidence has pointed to the role of adipokines and innate immune cells, in particular, adipose tissue macrophages, in the regulation of fat inflammation and glucose homeostasis. However, more recently, cells of the adaptive immune system, specifically B and T lymphocytes, have emerged as unexpected promoters and controllers of insulin resistance. These adaptive immune cells infiltrate obesity expanded VAT and through cytokine secretion and macrophage modulation dictate the extent of the local inflammatory response, thereby directly impacting insulin resistance. The remarkable ability of our adaptive immune system to regulate insulin sensitivity and metabolism has unmasked a novel physiological function of this system, and promises new diagnostic and therapeutic strategies to manage the disease. This review highlights critical roles of adipose tissue lymphocytes in governing glucose homeostasis.

  18. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity.

    PubMed

    Ostrand-Rosenberg, Suzanne

    2010-10-01

    Myeloid-derived suppressor cells (MDSC) accumulate in most cancer patients and experimental animals with cancer. They accumulate in response to pro-inflammatory mediators and they use a variety of mechanisms to block both innate and adaptive antitumor immunity. Because of their critical role in obstructing immune responses, MDSC are a strategic obstacle to immunotherapies that require activation of the host's cell-mediated and innate immune responses. Following a brief description of the factors that induce MDSC accumulation, this article reviews two newly discovered mechanisms that MDSC use to suppress the activation of CD4(+) and CD8(+) T cells. The first mechanism is MDSC sequestration of cysteine, an amino acid that T cells are unable to synthesize de novo and that they require for activation. The second mechanism is MDSC-mediated down-regulation of L: -selectin. T cells must have an L: -selectin(high) phenotype to home to lymph nodes and inflammatory sites where they encounter antigen and are activated. By down-regulating L: -selectin on T cells, MDSC perturb T cell trafficking patterns and thereby inhibit T cell activation. Given the complexity of conditions that regulate MDSC accumulation and the variety of suppressive mechanisms used by MDSC, it is essential to understand which conditions and mechanisms are dominant so MDSC accumulation and/or activity can be targeted in individual patients to minimize MDSC-induced immune suppression.

  19. Integrase-mediated spacer acquisition during CRISPR-Cas adaptive immunity.

    PubMed

    Nuñez, James K; Lee, Amy S Y; Engelman, Alan; Doudna, Jennifer A

    2015-03-12

    Bacteria and archaea insert spacer sequences acquired from foreign DNAs into CRISPR loci to generate immunological memory. The Escherichia coli Cas1-Cas2 complex mediates spacer acquisition in vivo, but the molecular mechanism of this process is unknown. Here we show that the purified Cas1-Cas2 complex integrates oligonucleotide DNA substrates into acceptor DNA to yield products similar to those generated by retroviral integrases and transposases. Cas1 is the catalytic subunit and Cas2 substantially increases integration activity. Protospacer DNA with free 3'-OH ends and supercoiled target DNA are required, and integration occurs preferentially at the ends of CRISPR repeats and at sequences adjacent to cruciform structures abutting AT-rich regions, similar to the CRISPR leader sequence. Our results demonstrate the Cas1-Cas2 complex to be the minimal machinery that catalyses spacer DNA acquisition and explain the significance of CRISPR repeats in providing sequence and structural specificity for Cas1-Cas2-mediated adaptive immunity.

  20. The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

    PubMed Central

    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

    2016-01-01

    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

  1. Crosstalk between Adaptive and Innate Immune Cells leads to High Quality Immune Protection at the Mucosal Borders

    PubMed Central

    Cheroutre, Hilde; Huang, Yujun

    2014-01-01

    Mucosal effector memory CD8 T cells are located at the epithelium and have a heightened and immediate effector function. By contrast, central memory T cells reside within lymphoid tissues and require proliferation and differentiation to become effector cells that migrate to epithelial surfaces. The accumulation of effector memory T cells at the pathogen entry site(s) is essential for protective immunity, but the mechanisms that drive the differentiation of memory cell subsets are poorly understood. We recently showed that CD8αα, induced selectively on the most highly activated primary CD8αβ T cells, together with its ligand, the thymic leukemia (TL) antigen, induced on mucosal antigen presenting cells and constitutively expressed on intestinal epithelial cells, serve as key components to mediate the selective accumulation of the fittest effector cells to form mucosal effector memory T cells. Therefore, the generation of mucosal effector memory is controlled by an innate-adaptive crosstalk that provides for host defense at the body’s largest interface. PMID:23456836

  2. 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.

  3. Stochastic stage-structured modeling of the adaptive immune system

    SciTech Connect

    Chao, D. L.; Davenport, M. P.; Forrest, S.; Perelson, Alan S.,

    2003-01-01

    We have constructed a computer model of the cytotoxic T lymphocyte (CTL) response to antigen and the maintenance of immunological memory. Because immune responses often begin with small numbers of cells and there is great variation among individual immune systems, we have chosen to implement a stochastic model that captures the life cycle of T cells more faithfully than deterministic models. Past models of the immune response have been differential equation based, which do not capture stochastic effects, or agent-based, which are computationally expensive. We use a stochastic stage-structured approach that has many of the advantages of agent-based modeling but is more efficient. Our model can provide insights into the effect infections have on the CTL repertoire and the response to subsequent infections.

  4. Molecular Mechanisms of Aging and Immune System Regulation in Drosophila

    PubMed Central

    Eleftherianos, Ioannis; Castillo, Julio Cesar

    2012-01-01

    Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span. PMID:22949833

  5. Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)

    PubMed Central

    Ghoreschi, Kamran; Jesson, Michael I.; Li, Xiong; Lee, Jamie L.; Ghosh, Sarbani; Alsup, Jason W.; Warner, James D.; Tanaka, Masao; Steward-Tharp, Scott M.; Gadina, Massimo; Thomas, Craig; Minnerly, John C.; Storer, Chad E.; LaBranche, Timothy P.; Radi, Zaher A.; Dowty, Martin E.; Head, Richard D.; Meyer, Debra M.; Kishore, Nandini; O'Shea, John J.

    2011-01-01

    Inhibitors of the JAK family of non-receptor tyrosine kinases have demonstrated clinical efficacy in rheumatoid arthritis and other inflammatory disorders; however, the precise mechanisms by which JAK inhibition improves inflammatory immune responses remain unclear. Here we examined the mode of action of tofacitinib (CP-690,550) on JAK/STAT signaling pathways involved in adaptive and innate immune responses. To determine the extent of inhibition of specific JAK/STAT-dependent pathways, we analyzed cytokine stimulation of mouse and human T cells in vitro. We also investigated the consequences of CP-690,550 treatment on Th cell differentiation of naïve murine CD4+ T cells. CP-690,550 inhibited IL-4-dependent Th2 cell differentiation, and interestingly also interfered with Th17 cell differentiation. Expression of IL-23 receptor and of the Th17 cytokines IL-17A, IL-17F and IL-22 were blocked when naïve Th cells were stimulated with IL-6 and IL-23. In contrast, IL-17A-production was enhanced when Th17 cells were differentiated in the presence of TGF-β. Moreover, CP-690,550 also prevented activation of STAT1, induction of T-bet and subsequent generation of Th1 cells. In a model of established arthritis, CP-690,550 rapidly improved disease by inhibiting production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. Furthermore, efficacy in this disease model correlated with inhibition of both JAK1 and JAK3 signaling pathways. CP-690,550 also modulated innate responses to LPS in vivo through a mechanism likely involving inhibition of STAT1 signaling. Thus, CP-690,550 may improve autoimmune diseases and prevent transplant rejection by suppressing the differentiation of pathogenic Th1 and Th17 cells, as well as innate immune cell signaling. PMID:21383241

  6. Immune suppressive mechanisms in the tumor microenvironment.

    PubMed

    Munn, David H; Bronte, Vincenzo

    2016-04-01

    Effective immunotherapy, whether by checkpoint blockade or adoptive cell therapy, is limited in most patients by a key barrier: the immunosuppressive tumor microenvironment. Suppression of tumor-specific T cells is orchestrated by the activity of a variety of stromal myeloid and lymphoid cells. These often display inducible suppressive mechanisms that are triggered by the same anti-tumor inflammatory response that the immunotherapy intends to create. Therefore, a more comprehensive understanding of how the immunosuppressive milieu develops and persists is critical in order to harness the full power of immunotherapy of cancer.

  7. Adaptive Immune Responses to Zika Virus Are Important for Controlling Virus Infection and Preventing Infection in Brain and Testes.

    PubMed

    Winkler, Clayton W; Myers, Lara M; Woods, Tyson A; Messer, Ronald J; Carmody, Aaron B; McNally, Kristin L; Scott, Dana P; Hasenkrug, Kim J; Best, Sonja M; Peterson, Karin E

    2017-03-22

    The recent association between Zika virus (ZIKV) and neurologic complications, including Guillain-Barré syndrome in adults and CNS abnormalities in fetuses, highlights the importance in understanding the immunological mechanisms controlling this emerging infection. Studies have indicated that ZIKV evades the human type I IFN response, suggesting a role for the adaptive immune response in resolving infection. However, the inability of ZIKV to antagonize the mouse IFN response renders the virus highly susceptible to circulating IFN in murine models. Thus, as we show in this article, although wild-type C57BL/6 mice mount cell-mediated and humoral adaptive immune responses to ZIKV, these responses were not required to prevent disease. However, when the type I IFN response of mice was suppressed, then the adaptive immune responses became critical. For example, when type I IFN signaling was blocked by Abs in Rag1(-/-) mice, the mice showed dramatic weight loss and ZIKV infection in the brain and testes. This phenotype was not observed in Ig-treated Rag1(-/-) mice or wild-type mice treated with anti-type I IFNR alone. Furthermore, we found that the CD8(+) T cell responses of pregnant mice to ZIKV infection were diminished compared with nonpregnant mice. It is possible that diminished cell-mediated immunity during pregnancy could increase virus spread to the fetus. These results demonstrate an important role for the adaptive immune response in the control of ZIKV infection and imply that vaccination may prevent ZIKV-related disease, particularly when the type I IFN response is suppressed as it is in humans.

  8. Innate and adaptive immune traits are differentially affected by genetic and environmental factors

    PubMed Central

    Mangino, Massimo; Roederer, Mario; Beddall, Margaret H.; Nestle, Frank O.; Spector, Tim D.

    2017-01-01

    The diversity and activity of leukocytes is controlled by genetic and environmental influences to maintain balanced immune responses. However, the relative contribution of environmental compared with genetic factors that affect variations in immune traits is unknown. Here we analyse 23,394 immune phenotypes in 497 adult female twins. 76% of these traits show a predominantly heritable influence, whereas 24% are mostly influenced by environment. These data highlight the importance of shared childhood environmental influences such as diet, infections or microbes in shaping immune homeostasis for monocytes, B1 cells, γδ T cells and NKT cells, whereas dendritic cells, B2 cells, CD4+ T and CD8+ T cells are more influenced by genetics. Although leukocyte subsets are influenced by genetics and environment, adaptive immune traits are more affected by genetics, whereas innate immune traits are more affected by environment. PMID:28054551

  9. Innate and adaptive antifungal immune responses: partners on an equal footing.

    PubMed

    Hamad, Mawieh

    2012-05-01

    Adaptive immunity has long been regarded as the major player in protection against most fungal infections. Mounting evidence suggest however, that both innate and adaptive responses intricately collaborate to produce effective antifungal protection. Dendritic cells (DCs) play an important role in initiating and orchestrating antifungal immunity; neutrophils, macrophages and other phagocytes also participate in recognising and eliminating fungal pathogens. Adaptive immunity provides a wide range of effector and regulatory responses against fungal infections. Th1 responses protect against most forms of mycoses but they associate with significant inflammation and limited pathogen persistence. By contrast, Th2 responses enhance persistence of and tolerance to fungal infections thus permitting the generation of long-lasting immunological memory. Although the role of Th17 cytokines in fungal immunity is not fully understood, they can enhance proinflammatory or anti-inflammatory responses or play a regulatory role in fungal immunity all depending on the pathogen, site/phase of infection and host immunostatus. T regulatory cells balance the activities of various Th cell subsets thereby permitting inflammation and protection on the one hand and allowing for tolerance and memory on the other. Here, recent developments in fungal immunity research are reviewed as means of tracing the emergence of a refined paradigm where innate and adaptive responses are viewed in the same light.

  10. On the evolutionary origin of the adaptive immune system--the adipocyte hypothesis.

    PubMed

    van Niekerk, Gustav; Engelbrecht, Anna-Mart

    2015-04-01

    Jawless vertebrates utilize a form of adaptive immunity that is functionally based on molecular effectors that are completely different from those of vertebrates. This observation raises an intriguing question: why did vertebrates, representing only 5% of all animals, twice evolve a system as complex as adaptive immunity? Theories aimed at identifying a selective pressure that would 'drive' the development of an adaptive immune system (AIS) fail to explain why invertebrates would not similarly develop an AIS. We argue that an AIS can only be implemented in a certain physiological context, i.e., that an AIS represents an unevolvable trait for invertebrates. The immune system is functionally integrated with other systems; therefore a preexisting physiological innovation unique to vertebrates may have acted as the prerequisite infrastructure that allowed the development of an AIS. We propose that future efforts should be directed toward identifying the evolutionary release that allowed the development of an adaptive immune system in vertebrates. In particular, the advent of specialized adipocytes might have expanded the metabolic scope of vertebrates, allowing the opportunistic incorporation of an AIS. However, physiological innovations, unique to (or more developed in) vertebrates, support the implementation of an AIS. Thus, understanding the interaction between systems (e.g. neural-immune-adipose connection) may illuminate our understanding regarding the perplexing immunological dimorphism within the animal kingdom.

  11. Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis

    NASA Astrophysics Data System (ADS)

    Mitchell, Michael J.; Webster, Jamie; Chung, Amanda; Guimarães, Pedro P. G.; Khan, Omar F.; Langer, Robert

    2017-03-01

    Physical forces affect tumour growth, progression and metastasis. Here, we develop polymeric mechanical amplifiers that exploit in vitro and in vivo physical forces to increase immune cytokine-mediated tumour cell apoptosis. Mechanical amplifiers, consisting of biodegradable polymeric particles tethered to the tumour cell surface via polyethylene glycol linkers, increase the apoptotic effect of an immune cytokine on tumour cells under fluid shear exposure by as much as 50% compared with treatment under static conditions. We show that targeted polymeric particles delivered to tumour cells in vivo amplify the apoptotic effect of a subsequent treatment of immune cytokine, reduce circulating tumour cells in blood and overall tumour cell burden by over 90% and reduce solid tumour growth in combination with the antioxidant resveratrol. The work introduces a potentially new application for a broad range of micro- and nanoparticles to maximize receptor-mediated signalling and function in the presence of physical forces.

  12. Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis

    PubMed Central

    Mitchell, Michael J.; Webster, Jamie; Chung, Amanda; Guimarães, Pedro P. G.; Khan, Omar F.; Langer, Robert

    2017-01-01

    Physical forces affect tumour growth, progression and metastasis. Here, we develop polymeric mechanical amplifiers that exploit in vitro and in vivo physical forces to increase immune cytokine-mediated tumour cell apoptosis. Mechanical amplifiers, consisting of biodegradable polymeric particles tethered to the tumour cell surface via polyethylene glycol linkers, increase the apoptotic effect of an immune cytokine on tumour cells under fluid shear exposure by as much as 50% compared with treatment under static conditions. We show that targeted polymeric particles delivered to tumour cells in vivo amplify the apoptotic effect of a subsequent treatment of immune cytokine, reduce circulating tumour cells in blood and overall tumour cell burden by over 90% and reduce solid tumour growth in combination with the antioxidant resveratrol. The work introduces a potentially new application for a broad range of micro- and nanoparticles to maximize receptor-mediated signalling and function in the presence of physical forces. PMID:28317839

  13. 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.

  14. 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

  15. The p50 Subunit of NF-κB Orchestrates Dendritic Cell Lifespan and Activation of Adaptive Immunity

    PubMed Central

    Larghi, Paola; Porta, Chiara; Riboldi, Elena; Totaro, Maria Grazia; Carraro, Lorenzo; Orabona, Ciriana; Sica, Antonio

    2012-01-01

    Dendritic cells play a central role in keeping the balance between immunity and immune tolerance. A key factor in this equilibrium is the lifespan of DC, as its reduction restrains antigen availability leading to termination of immune responses. Here we show that lipopolysaccharide-driven DC maturation is paralleled by increased nuclear levels of p50 NF-κB, an event associated with DC apoptosis. Lack of p50 in murine DC promoted increased lifespan, enhanced level of maturation associated with increased expression of the proinflammatory cytokines IL-1, IL-18 and IFN-β, enhanced capacity of activating and expanding CD4+ and CD8+ T cells in vivo and decreased ability to induce differentiation of FoxP3+ regulatory T cells. In agreement, vaccination of melanoma-bearing mice with antigen-pulsed LPS-treated p50−/− BM-DC boosted antitumor immunity and inhibition of tumor growth. We propose that nuclear accumulation of the p50 NF-κB subunit in DC, as occurring during lipopolysaccharide-driven maturation, is a homeostatic mechanism tuning the balance between uncontrolled activation of adaptive immunity and immune tolerance. PMID:23049782

  16. Type Six Secretion System of Bordetella bronchiseptica and Adaptive Immune Components Limit Intracellular Survival During Infection

    PubMed Central

    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

  17. 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.

  18. Regulating the adaptive immune response to blood-stage malaria: role of dendritic cells and CD4⁺Foxp3⁺ regulatory T cells.

    PubMed

    Stevenson, Mary M; Ing, Rebecca; Berretta, Floriana; Miu, Jenny

    2011-01-01

    Although a clearer understanding of the underlying mechanisms involved in protection and immunopathology during blood-stage malaria has emerged, the mechanisms involved in regulating the adaptive immune response especially those required to maintain a balance between beneficial and deleterious responses remain unclear. Recent evidence suggests the importance of CD11c⁺ dendritic cells (DC) and CD4⁺Foxp3⁺ regulatory T cells in regulating immune responses during infection and autoimmune disease, but information concerning the contribution of these cells to regulating immunity to malaria is limited. Here, we review recent findings from our laboratory and others in experimental models of malaria in mice and in Plasmodium-infected humans on the roles of DC and natural regulatory T cells in regulating adaptive immunity to blood-stage malaria.

  19. Immune mechanisms in atherosclerosis, especially in diabetes type 2.

    PubMed

    Frostegård, Johan

    2013-10-29

    Atherosclerosis and ensuing cardiovascular disease (CVD) are major complications of diabetes type 2. Atherosclerosis is a chronic inflammatory condition involving immunocompetent cells of different types present in the lesions. Even though inflammation and immune activation may be more pronounced in atherosclerosis in diabetes type 2, there does not appear to be any major differences between diabetics and non-diabetics. Similar factors are thus implicated in atherosclerosis-associated immune activation in both groups. The cause of immune activation is not known and different mutually non-exclusive possibilities exist. Oxidized and/or enzymatically modified forms of low-density lipoprotein (OxLDL) and dead cells are present in atherosclerotic plaques. OxLDL could play a role, being pro-inflammatory and immunostimulatory as it activates T-cells and is cytotoxic at higher concentrations. Inflammatory phospholipids in OxLDL are implicated, with phosphorylcholine (PC) as one of the exposed antigens. Antibodies against PC (anti-PC) are anti-atherogenic in mouse studies, and anti-PC is negatively associated with development of atherosclerosis and CVD in humans. Bacteria and virus have been discussed as potential causes of immune activation, but it has been difficult to find direct evidence supporting this hypothesis, and antibiotic trials in humans have been negative or inconclusive. Heat shock proteins (HSP) could be one major target for atherogenic immune reactions. More direct causes of plaque rupture include cytokines such as interleukin 1β (IL-1β), tumor necrosis factor (TNF), and also lipid mediators as leukotrienes. In addition, in diabetes, hyperglycemia and oxidative stress appear to accelerate the development of atherosclerosis, one mechanism could be via promotion of immune reactions. To prove that immune reactions are causative of atherosclerosis and CVD, further studies with immune-modulatory treatments are needed.

  20. Aging of the Immune System. Mechanisms and Therapeutic Targets.

    PubMed

    Weyand, Cornelia M; Goronzy, Jörg J

    2016-12-01

    Beginning with the sixth decade of life, the human immune system undergoes dramatic aging-related changes, which continuously progress to a state of immunosenescence. The aging immune system loses the ability to protect against infections and cancer and fails to support appropriate wound healing. Vaccine responses are typically impaired in older individuals. Conversely, inflammatory responses mediated by the innate immune system gain in intensity and duration, rendering older individuals susceptible to tissue-damaging immunity and inflammatory disease. Immune system aging functions as an accelerator for other age-related pathologies. It occurs prematurely in some clinical conditions, most prominently in patients with the autoimmune syndrome rheumatoid arthritis (RA); and such patients serve as an informative model system to study molecular mechanisms of immune aging. T cells from patients with RA are prone to differentiate into proinflammatory effector cells, sustaining chronic-persistent inflammatory lesions in the joints and many other organ systems. RA T cells have several hallmarks of cellular aging; most importantly, they accumulate damaged DNA. Because of deficiency of the DNA repair kinase ataxia telangiectasia mutated, RA T cells carry a higher burden of DNA double-strand breaks, triggering cell-indigenous stress signals that shift the cell's survival potential and differentiation pattern. Immune aging in RA T cells is also associated with metabolic reprogramming; specifically, with reduced glycolytic flux and diminished ATP production. Chronic energy stress affects the longevity and the functional differentiation of older T cells. Altered metabolic patterns provide opportunities to therapeutically target the immune aging process through metabolic interference.

  1. Role of Vanadium in Cellular and Molecular Immunology: Association with Immune-Related Inflammation and Pharmacotoxicology Mechanisms

    PubMed Central

    Tsave, Olga; Petanidis, Savvas; Kioseoglou, Efrosini; Yavropoulou, Maria P.; Yovos, John G.; Anestakis, Doxakis; Tsepa, Androniki; Salifoglou, Athanasios

    2016-01-01

    Over the last decade, a diverse spectrum of vanadium compounds has arisen as anti-inflammatory therapeutic metallodrugs targeting various diseases. Recent studies have demonstrated that select well-defined vanadium species are involved in many immune-driven molecular mechanisms that regulate and influence immune responses. In addition, advances in cell immunotherapy have relied on the use of metallodrugs to create a “safe,” highly regulated, environment for optimal control of immune response. Emerging findings include optimal regulation of B/T cell signaling and expression of immune suppressive or anti-inflammatory cytokines, critical for immune cell effector functions. Furthermore, in-depth perusals have explored NF-κB and Toll-like receptor signaling mechanisms in order to enhance adaptive immune responses and promote recruitment or conversion of inflammatory cells to immunodeficient tissues. Consequently, well-defined vanadium metallodrugs, poised to access and resensitize the immune microenvironment, interact with various biomolecular targets, such as B cells, T cells, interleukin markers, and transcription factors, thereby influencing and affecting immune signaling. A synthetically formulated and structure-based (bio)chemical reactivity account of vanadoforms emerges as a plausible strategy for designing drugs characterized by selectivity and specificity, with respect to the cellular molecular targets intimately linked to immune responses, thereby giving rise to a challenging field linked to the development of immune system vanadodrugs. PMID:27190573

  2. Role of Vanadium in Cellular and Molecular Immunology: Association with Immune-Related Inflammation and Pharmacotoxicology Mechanisms.

    PubMed

    Tsave, Olga; Petanidis, Savvas; Kioseoglou, Efrosini; Yavropoulou, Maria P; Yovos, John G; Anestakis, Doxakis; Tsepa, Androniki; Salifoglou, Athanasios

    2016-01-01

    Over the last decade, a diverse spectrum of vanadium compounds has arisen as anti-inflammatory therapeutic metallodrugs targeting various diseases. Recent studies have demonstrated that select well-defined vanadium species are involved in many immune-driven molecular mechanisms that regulate and influence immune responses. In addition, advances in cell immunotherapy have relied on the use of metallodrugs to create a "safe," highly regulated, environment for optimal control of immune response. Emerging findings include optimal regulation of B/T cell signaling and expression of immune suppressive or anti-inflammatory cytokines, critical for immune cell effector functions. Furthermore, in-depth perusals have explored NF-κB and Toll-like receptor signaling mechanisms in order to enhance adaptive immune responses and promote recruitment or conversion of inflammatory cells to immunodeficient tissues. Consequently, well-defined vanadium metallodrugs, poised to access and resensitize the immune microenvironment, interact with various biomolecular targets, such as B cells, T cells, interleukin markers, and transcription factors, thereby influencing and affecting immune signaling. A synthetically formulated and structure-based (bio)chemical reactivity account of vanadoforms emerges as a plausible strategy for designing drugs characterized by selectivity and specificity, with respect to the cellular molecular targets intimately linked to immune responses, thereby giving rise to a challenging field linked to the development of immune system vanadodrugs.

  3. The potential impact of antifungal drug resistance mechanisms on the host immune response to Candida

    PubMed Central

    Lewis, Russell E.; Viale, Pierluigi; Kontoyiannis, Dimitrios P.

    2012-01-01

    A large number of studies have been published over the last two decades examining molecular mechanisms of antifungal resistance in Candida species. However, few of these studies have explored how such mechanisms influence the host immune response to this opportunistic pathogen. With recent advances in our understanding of host immunity to Candida, a body of emerging literature has begun to explore how intrinsic and adaptive resistance mechanisms in Candida alter host immune system evasion and detection, which could have important implications for understanding (1) why certain resistance mechanisms and Candida species predominate in certain patient populations, (2) the biological context for understanding why high in vitro levels of resistance in may not necessarily correlate with risk of drug failure in vivo and (3) insight into effective immunotherapeutic strategies for combatting Candida resistance. Although this area of research is still in its infancy, two themes are emerging: First, the immunoevasion and intracellular persistence of C. glabrata may be a key factor in the capability of this species to persist in the course of multiple antifungal treatments and develop multidrug resistance. Second, changes in the cell wall associated with antifungal resistance often favor evasion for the host immune response. PMID:22722245

  4. The immune system as a biomonitor: explorations in innate and adaptive immunity.

    PubMed

    Thomas, Niclas; Heather, James; Pollara, Gabriel; Simpson, Nandi; Matjeka, Theres; Shawe-Taylor, John; Noursadeghi, Mahdad; Chain, Benjamin

    2013-04-06

    The human immune system has a highly complex, multi-layered structure which has evolved to detect and respond to changes in the internal microenvironment of the body. Recognition occurs at the molecular or submolecular scale, via classical reversible receptor-ligand interactions, and can lead to a response with great sensitivity and speed. Remarkably, recognition is coupled to memory, such that responses are modulated by events which occurred years or even decades before. Although the immune system in general responds differently and more vigorously to stimuli entering the body from the outside (e.g. infections), this is an emergent property of the system: many of the recognition molecules themselves have no inherent bias towards external stimuli (non-self) but also bind targets found within the body (self). It is quite clear that the immune response registers pathophysiological changes in general. Cancer, wounding and chronic tissue injury are some obvious examples. Against this background, the immune system 'state' tracks the internal processes of the body, and is likely to encode information regarding both current and past disease processes. Moreover, the distributed nature of most immune responses (e.g. typically involving lymphoid tissue, non-lymphoid tissue, bone marrow, blood, extracellular interstitial spaces, etc.) means that many of the changes associated with immune responses are manifested systemically, and specifically can be detected in blood. This provides a very convenient route to sampling immune cells. We consider two different and complementary ways of querying the human immune 'state' using high-dimensional genomic screening methodologies, and discuss the potentials of these approaches and some of the technological and computational challenges to be overcome.

  5. Innate immunity regulates adaptive immune response: lessons learned from studying the interplay between NK and CD8+ T cells during MCMV infection.

    PubMed

    Mitrović, Maja; Arapović, Jurica; Traven, Luka; Krmpotić, Astrid; Jonjić, Stipan

    2012-11-01

    Natural killer (NK) cells play a crucial role in early immune response against cytomegalovirus infection. A large and mounting body of data indicate that these cells are involved in the regulation of the adaptive immune response as well. By using mouse cytomegalovirus (MCMV) as a model, several groups provided novel insights into the role of NK cells in the development and kinetics of antiviral CD8(+) T cell response. Depending on infection conditions, virus strain and the genetic background of mice used, NK cells are either positive or negative regulators of the CD8(+) T cell response. At present, there is no unique explanation for the observed differences between various experimental systems used. In this review we discuss the mechanisms involved in the interplay between NK and CD8(+) T cells in the early control of MCMV infection.

  6. Innate immunity regulates adaptive immune response: lessons learned from studying the interplay between NK and CD8+ T cells during MCMV infection

    PubMed Central

    Mitrović, Maja; Arapović, Jurica; Traven, Luka; Krmpotić, Astrid; Jonjić, Stipan

    2012-01-01

    Natural killer (NK) cells play a crucial role in early immune response against cytomegalovirus infection. A large and mounting body of data indicate that these cells are involved in the regulation of the adaptive immune response as well. By using mouse cytomegalovirus (MCMV) as a model, several groups provided novel insights into the role of NK cells in the development and kinetics of antiviral CD8+ T cell response. Depending on infection conditions, virus strain and the genetic background of mice used, NK cells are either positive or negative regulators of the CD8+ T cell response. At present, there is no unique explanation for the observed differences between various experimental systems used. In this review we discuss the mechanisms involved in the interplay between NK and CD8+ T cells in the early control of MCMV infection. PMID:22965169

  7. Resident memory CD8 T cells trigger protective innate and adaptive immune responses

    PubMed Central

    Schenkel, Jason M.; Fraser, Kathryn A.; Beura, Lalit K.; Pauken, Kristen E.; Vezys, Vaiva; Masopust, David

    2015-01-01

    The pathogen recognition theory dictates that upon viral infection, the innate immune system first detects microbial products, and then responds by providing instructions to adaptive CD8 T cells. Here, we show in mice that resident memory CD8 T cells (TRM), non-recirculating cells located at common sites of infection, can achieve near sterilizing immunity against viral infections by reversing this flow of information. Upon antigen re-sensitization within the mouse female reproductive mucosae, CD8+ TRM secrete cytokines that trigger rapid adaptive and innate immune responses including local humoral responses, maturation of local dendritic cells, and activation of natural killer cells. This provided near sterilizing immunity against an antigenically unrelated viral infection. Thus, CD8+ TRM rapidly trigger an antiviral state by amplifying receptor-derived signals from previously encountered pathogens. PMID:25170049

  8. Ontogeny of innate and adaptive immune defense components in free-living tree swallows, Tachycineta bicolor.

    PubMed

    Palacios, Maria G; Cunnick, Joan E; Vleck, David; Vleck, Carol M

    2009-04-01

    Little is known about the development of immune function in wild animals. We investigated the ontogeny of immune defense in a free-living bird, the tree swallow. We assessed total and differential leukocyte counts, natural antibodies, complement activity, in vivo skin swelling response, and in vitro lymphocyte proliferation and compared the levels of development between nestlings and young adults. We also assessed whether body condition explained variation in these immune components. We found some support for the prediction that innate defenses, which do not need to generate a broad repertoire of specific receptors, would reach adult levels earlier than adaptive defenses. In contrast, we found limited support for the prediction that adaptive defenses, which are thought to be more costly to develop, would be more related to body condition than innate defenses. We discuss our findings in the context of other studies on the ontogeny of immune function.

  9. 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.

  10. 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

  11. Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions.

    PubMed

    Kravchenko, Julia; Corsini, Emanuela; Williams, Marc A; Decker, William; Manjili, Masoud H; Otsuki, Takemi; Singh, Neetu; Al-Mulla, Faha; Al-Temaimi, Rabeah; Amedei, Amedeo; Colacci, Anna Maria; Vaccari, Monica; Mondello, Chiara; Scovassi, A Ivana; Raju, Jayadev; Hamid, Roslida A; Memeo, Lorenzo; Forte, Stefano; Roy, Rabindra; Woodrick, Jordan; Salem, Hosni K; Ryan, Elizabeth P; Brown, Dustin G; Bisson, William H; Lowe, Leroy; Lyerly, H Kim

    2015-06-01

    An increasing number of studies suggest an important role of host immunity as a barrier to tumor formation and progression. Complex mechanisms and multiple pathways are involved in evading innate and adaptive immune responses, with a broad spectrum of chemicals displaying the potential to adversely influence immunosurveillance. The evaluation of the cumulative effects of low-dose exposures from the occupational and natural environment, especially if multiple chemicals target the same gene(s) or pathway(s), is a challenge. We reviewed common environmental chemicals and discussed their potential effects on immunosurveillance. Our overarching objective was to review related signaling pathways influencing immune surveillance such as the pathways involving PI3K/Akt, chemokines, TGF-β, FAK, IGF-1, HIF-1α, IL-6, IL-1α, CTLA-4 and PD-1/PDL-1 could individually or collectively impact immunosurveillance. A number of chemicals that are common in the anthropogenic environment such as fungicides (maneb, fluoxastrobin and pyroclostrobin), herbicides (atrazine), insecticides (pyridaben and azamethiphos), the components of personal care products (triclosan and bisphenol A) and diethylhexylphthalate with pathways critical to tumor immunosurveillance. At this time, these chemicals are not recognized as human carcinogens; however, it is known that they these chemicalscan simultaneously persist in the environment and appear to have some potential interfere with the host immune response, therefore potentially contributing to promotion interacting with of immune evasion mechanisms, and promoting subsequent tumor growth and progression.

  12. Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions

    PubMed Central

    Kravchenko, Julia; Corsini, Emanuela; Williams, Marc A.; Decker, William; Manjili, Masoud H.; Otsuki, Takemi; Singh, Neetu; Al-Mulla, Faha; Al-Temaimi, Rabeah; Amedei, Amedeo; Colacci, Anna Maria; Vaccari, Monica; Mondello, Chiara; Scovassi, A. Ivana; Raju, Jayadev; Hamid, Roslida A.; Memeo, Lorenzo; Forte, Stefano; Roy, Rabindra; Woodrick, Jordan; Salem, Hosni K.; Ryan, Elizabeth P.; Brown, Dustin G.; Lowe, Leroy; Lyerly, H.Kim

    2015-01-01

    An increasing number of studies suggest an important role of host immunity as a barrier to tumor formation and progression. Complex mechanisms and multiple pathways are involved in evading innate and adaptive immune responses, with a broad spectrum of chemicals displaying the potential to adversely influence immunosurveillance. The evaluation of the cumulative effects of low-dose exposures from the occupational and natural environment, especially if multiple chemicals target the same gene(s) or pathway(s), is a challenge. We reviewed common environmental chemicals and discussed their potential effects on immunosurveillance. Our overarching objective was to review related signaling pathways influencing immune surveillance such as the pathways involving PI3K/Akt, chemokines, TGF-β, FAK, IGF-1, HIF-1α, IL-6, IL-1α, CTLA-4 and PD-1/PDL-1 could individually or collectively impact immunosurveillance. A number of chemicals that are common in the anthropogenic environment such as fungicides (maneb, fluoxastrobin and pyroclostrobin), herbicides (atrazine), insecticides (pyridaben and azamethiphos), the components of personal care products (triclosan and bisphenol A) and diethylhexylphthalate with pathways critical to tumor immunosurveillance. At this time, these chemicals are not recognized as human carcinogens; however, it is known that they these chemicalscan simultaneously persist in the environment and appear to have some potential interfere with the host immune response, therefore potentially contributing to promotion interacting with of immune evasion mechanisms, and promoting subsequent tumor growth and progression. PMID:26002081

  13. Chagas’ disease: an update on immune mechanisms and therapeutic strategies

    PubMed Central

    Boscardin, Silvia Beatriz; Torrecilhas, Ana Claudia Troccoli; Manarin, Romina; Revelli, Silvia; Rey, Elena Gonzalez; Tonelli, Renata Rosito; Silber, Ariel Mariano

    2010-01-01

    Abstract The final decade of the 20th century was marked by an alarming resurgence in infectious diseases caused by tropical parasites belonging to the kinetoplastid protozoan order. Among the pathogenic trypanosomatids, some species are of particular interest due to their medical importance. These species include the agent responsible for Chagas’ disease, Trypanosoma cruzi. Approximately 8 to 10 million people are infected in the Americas, and approximately 40 million are at risk. In the present review, we discuss in detail the immune mechanisms elicited during infection by T. cruzi and the effects of chemotherapy in controlling parasite proliferation and on the host immune system. PMID:20070438

  14. A mechanism for trauma induced muscle wasting and immune dysfunction

    NASA Astrophysics Data System (ADS)

    Madihally, S.; Toner, M.; Yarmush, M.; Mitchell, R.

    A diverse physiological conditions lead to a hypercatabolic state marked by the loss of proteins, primarily derived from skeletal muscle. The sustained loss of proteins results in loss of muscle mass and strength, poor healing, and long-term hospitalization. These problems are further compounded by the deterioration of immunity to infection which is a leading cause of morbidity and mortality of traumatic patients. In an attempt to understand the signal propagation mechanism(s), we tested the role of Interferon-? (IFN-? ) in an animal burn injury model; IFN-? is best conceptualized as a macrophage activating protein and known to modulate a variety of intracellular processes potentially relevant to muscle wasting and immune dysfunction. Mice congenitally -deficient in IFN-? , and IFN-? -Receptor, and wild type (WT) animals treated with IFN-? neutralizing antibody received either a 20% total body surface area burn or a control sham treatment. At days 1, 2, and 7 following treatment, skeletal muscle, peripheral blood, and spleen were harvested from both groups. Overall body weight, protein turnovers, changes in the lymphocyte subpopulations and alterations in the major histocompatibility complex I expression (MHC I) and proliferation capacity of lymphocytes was measured using mixed lymphocyte reaction (MLR). These results indicate that we can prevent both muscle wasting and immune dysfunction. Based on these observations and our previous other animal model results (using insulin therapy), a novel mechanism of interactions leading to muscle wasting and immune dysfunction will be discussed. Further, implications of these findings on future research and clinical therapies will be discussed in detail.

  15. Targeting the TLR9-MyD88 pathway in the regulation of adaptive immune responses

    PubMed Central

    Huang, Xiaopei; Yang, Yiping

    2010-01-01

    IMPORTANCE OF THE FIELD Toll-like receptors (TLRs) are innate immune receptors critical in the innate immune defense against invading pathogens. Recent advances also reveal a crucial role for TLRs in shaping adaptive immune responses, conferring a potential therapeutic value to their modulation in the treatment of diseases. AREAS COVERED IN THIS REVIEW The aim of this review is to discuss TLR9, the TLR9-MyD88 signaling pathway and its role in regulation of adaptive immune responses, as well as potential therapeutic implications by targeting this pathway. WHAT THE READER WILL GAIN This review shows that the TLR9-MyD88 signaling pathway plays a critical role in promoting adaptive immune responses and that modulation of this pathway may have enormous therapeutic potential in enhancing vaccine potency, controlling autoimmunity, as well as improving the outcome of viral vector-mediated gene therapy. TAKE HOME MESSAGE Although TLR9 agonists have been used as adjuvants for enhancing vaccine potency, further exploitation of the TLR9-MyD88 pathway and its dynamic interaction with the immune system in vivo is needed to provide more effective therapeutic inventions in the design of vaccines for infectious diseases, allergies and cancer, in the control of autoimmunity, as well as in the improvement of viral vector-mediated gene therapy. PMID:20560798

  16. 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.

  17. Platelet CD40L at the interface of adaptive immunity

    PubMed Central

    Elzey, Bennett D.; Ratliff, Timothy L.; Sowa, Jennifer M.; Crist, Scott A.

    2010-01-01

    Initiated by the finding that platelets express functional CD40 ligand (CD40L, CD154), many new roles for platelets have been discovered in unanticipated areas, including the immune response. When current literature is considered as a whole, the picture that is emerging begins to show that platelets are able to significantly affect, for better or worse, the overall health and condition of the mammalian host. Animal models have made significant contributions to our expanding knowledge of platelet function, much of which is anticipated to be clinically relevant. While still mostly circumstantial, the evidence supports a critical role for CD40L in many normal and disease processes. PMID:21075431

  18. 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.

  19. 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

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

    PubMed

    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.

  1. ZAP70: a master regulator of adaptive immunity.

    PubMed

    Fischer, Alain; Picard, Capucine; Chemin, Karine; Dogniaux, Stéphanie; le Deist, Françoise; Hivroz, Claire

    2010-06-01

    The protein tyrosine kinase ZAP70 became the subject of intense scrutiny in the early nineties, when ZAP70 mutations were characterized in several young patients presenting with severe T cell immunodeficiencies. The association of a lack of expression of ZAP70 with an immunodeficiency consisting in a markedly reduced T lymphocyte-mediated immunity highlighted the crucial role of this tyrosine kinase in T cell development and function. This discovery was soon accompanied by the characterization of the substrates of ZAP70 and the signalling cascades that depend on ZAP70 activity. These studies demonstrated that ZAP70 was indeed at the crossroad of several signalling pathways that control T lymphocyte development and function. Recently, a revival of interest for this protein came again from studies associating abnormal ZAP70 expression with pathological conditions. Some chronic lymphocytic leukemia B cells were shown to express ZAP70, and this expression was correlated with bad prognosis. Mouse models also revealed that partial defects in ZAP70 activity can be associated with autoimmunity. These last results suggested that ZAP70 is involved in the fine balance between immunity and tolerance. In this review, we will discuss the role of ZAP70 in T cell activation and focus on what we learnt from pathological conditions associated with defective expression or activity of the ZAP70 kinase.

  2. Advances on molecular mechanism of the adaptive evolution of Chiroptera (bats).

    PubMed

    Yunpeng, Liang; Li, Yu

    2015-01-01

    As the second biggest animal group in mammals, Chiroptera (bats) demonstrates many unique adaptive features in terms of flight, echolocation, auditory acuity, feeding habit, hibernation and immune defense, providing an excellent system for understanding the molecular basis of how organisms adapt to the living environments encountered. In this review, we summarize the researches on the molecular mechanism of the adaptive evolution of Chiroptera, especially the recent researches at the genome levels, suggesting a far more complex evolutionary pattern and functional diversity than previously thought. In the future, along with the increasing numbers of Chiroptera species genomes available, new evolutionary patterns and functional divergence will be revealed, which can promote the further understanding of this animal group and the molecular mechanism of adaptive evolution.

  3. Tumor-derived γδ regulatory T cells suppress innate and adaptive immunity through the induction of immunosenescence.

    PubMed

    Ye, Jian; Ma, Chunling; Hsueh, Eddy C; Eickhoff, Christopher S; Zhang, Yanping; Varvares, Mark A; Hoft, Daniel F; Peng, Guangyong

    2013-03-01

    Fundamentally understanding the suppressive mechanisms used by different subsets of tumor-infiltrating regulatory T (Treg) cells is critical for the development of effective strategies for antitumor immunotherapy. γδ Treg cells have recently been identified in human diseases including cancer. However, the suppressive mechanisms and functional regulations of this new subset of unconventional Treg cells are largely unknown. In the current studies, we explored the suppressive mechanism(s) used by breast tumor-derived γδ Treg cells on innate and adaptive immunity. We found that γδ Treg cells induced immunosenescence in the targeted naive and effector T cells, as well as dendritic cells (DCs). Furthermore, senescent T cells and DCs induced by γδ Treg cells had altered phenotypes and impaired functions and developed potent suppressive activities, further amplifying the immunosuppression mediated by γδ Treg cells. In addition, we demonstrated that manipulation of TLR8 signaling in γδ Treg cells can block γδ Treg-induced conversion of T cells and DCs into senescent cells in vitro and in vivo. Our studies identify the novel suppressive mechanism mediated by tumor-derived γδ Treg cells on innate and adaptive immunity, which should be critical for the development of strong and innovative approaches to reverse the tumor-suppressive microenvironment and improve effects of immunotherapy.

  4. Solution-adaptive finite element method in computational fracture mechanics

    NASA Technical Reports Server (NTRS)

    Min, J. B.; Bass, J. M.; Spradley, L. W.

    1993-01-01

    Some recent results obtained using solution-adaptive finite element method in linear elastic two-dimensional fracture mechanics problems are presented. The focus is on the basic issue of adaptive finite element method for validating the applications of new methodology to fracture mechanics problems by computing demonstration problems and comparing the stress intensity factors to analytical results.

  5. 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.

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

    PubMed Central

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

    2016-01-01

    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

  7. Cell mechanics and immune system link up to fight infections

    NASA Astrophysics Data System (ADS)

    Ekpenyong, Andrew; Man, Si Ming; Tourlomousis, Panagiotis; Achouri, Sarra; Cammarota, Eugenia; Hughes, Katherine; Rizzo, Alessandro; Ng, Gilbert; Guck, Jochen; Bryant, Clare

    2015-03-01

    Infectious diseases, in which pathogens invade and colonize host cells, are responsible for one third of all mortality worldwide. Host cells use special proteins (immunoproteins) and other molecules to fight viral and bacterial invaders. The mechanisms by which immunoproteins enable cells to reduce bacterial loads and survive infections remain unclear. Moreover, during infections, some immunoproteins are known to alter the cytoskeleton, the structure that largely determines cellular mechanical properties. We therefore used an optical stretcher to measure the mechanical properties of primary immune cells (bone marrow derived macrophages) during bacterial infection. We found that macrophages become stiffer upon infection. Remarkably, macrophages lacking the immunoprotein, NLR-C4, lost the stiffening response to infection. This in vitro result correlates with our in vivo data whereby mice lacking NLR-C4 have more lesions and hence increased bacterial distribution and spread. Thus, the immune-protein-dependent increase in cell stiffness in response to bacterial infection (in vitro result) seems to have a functional role in the system level fight against pathogens (in vivo result). We will discuss how this functional link between cell mechanical properties and innate immunity, effected by actin polymerization, reduces the spread of infection.

  8. Innate and adaptive immunity against porcine reproductive and respiratory syndrome virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 s...

  9. Human Immunodeficiency Virus-1 Inhibition of Immunoamphisomes in Dendritic Cells Impairs Early Innate and Adaptive Immune Responses

    PubMed Central

    Blanchet, Fabien P.; Moris, Arnaud; Nikolic, Damjan S.; Lehmann, Martin; Cardinaud, Sylvain; Stalder, Romaine; Garcia, Eduardo; Dinkins, Christina; Leuba, Florence; Wu, Li; Schwartz, Olivier; Deretic, Vojo; Piguet, Vincent

    2010-01-01

    SUMMARY Dendritic cells (DCs) in mucosal surfaces are early targets for human immunodeficiency virus-1 (HIV-1). DCs mount rapid and robust immune responses upon pathogen encounter. However, immune response in the early events of HIV-1 transmission appears limited, suggesting that HIV-1 evade early immune control by DCs. We report that HIV-1 induces a rapid shutdown of autophagy and immunoamphisomes in DCs. HIV-1 envelope activated the mammalian target of rapamycin pathway in DCs, leading to autophagy exhaustion. HIV-1-induced inhibition of autophagy in DC increased cell-associated HIV-1 and transfer of HIV-1 infection to CD4+ T cells. HIV-1-mediated downregulation of autophagy in DCs impaired innate and adaptive immune responses. Immunoamphisomes in DCs engulf incoming pathogens and appear to amplify pathogen degradation as well as Toll-like receptor responses and antigen presentation. The findings that HIV-1 downregulates autophagy and impedes immune functions of DCs represent a pathogenesis mechanism that can be pharmacologically countered with therapeutic and prophylactic implications. PMID:20451412

  10. Do common mechanisms of adaptation mediate color discrimination and appearance? Contrast adaptation

    NASA Astrophysics Data System (ADS)

    Hillis, James M.; Brainard, David H.

    2007-08-01

    Are effects of background contrast on color appearance and sensitivity controlled by the same mechanism of adaptation? We examined the effects of background color contrast on color appearance and on color-difference sensitivity under well-matched conditions. We linked the data using Fechner's hypothesis that the rate of apparent stimulus change is proportional to sensitivity and examined a family of parametric models of adaptation. Our results show that both appearance and discrimination are consistent with the same mechanism of adaptation.

  11. Do common mechanisms of adaptation mediate color discrimination and appearance? Contrast adaptation.

    PubMed

    Hillis, James M; Brainard, David H

    2007-08-01

    Are effects of background contrast on color appearance and sensitivity controlled by the same mechanism of adaptation? We examined the effects of background color contrast on color appearance and on color-difference sensitivity under well-matched conditions. We linked the data using Fechner's hypothesis that the rate of apparent stimulus change is proportional to sensitivity and examined a family of parametric models of adaptation. Our results show that both appearance and discrimination are consistent with the same mechanism of adaptation.

  12. Physiological organization of immune response based on the homeostatic mechanism of matrix reprogramming: implication in tumor and biotechnology.

    PubMed

    Malyshev, Igor Yu; Manukhina, Eugenia B; Malyshev, Yuri I

    2014-06-01

    It is accepted that the immune system responds to pathogens with activation of antigen-independent innate and antigen-dependent adaptive immunity. However many immune events do not fit or are even inconsistent with this notion. We developed a new homeostatic model of the immune response. This model consists of four units: a sensor, a regulator, an effector and a rehabilitator. The sensor, macrophages or lymphocytes, recognize pathogenic cells and generate alarm signals. The regulator, antigen-presenting cells, Тregs and myeloid-derived suppressor cells, evaluate the signals and together with sensor cells program the effector. The effector, programmed macrophages and lymphocytes, eliminate the pathogenic cells. The rehabilitator, M2 macrophages, restrict inflammation, provide angiogenesis and reparation of tissue damage, and restore the homeostasis. We suggest the terms "immune matrix" for a biological template of immune responses to pathogens and "matrix reprogramming" for the interdependent reprogramming of different cells in the matrix. In an adequate immune response, the matrix forms a negative feedback mechanism to support the homeostasis. We defined the cellular and phenotypic composition of a tumor immune matrix. A tumor reprograms the homeostatic negative feedback mechanism of matrix into a pathogenic positive feedback mechanism. M2 macrophages play a key role in this transformation. Therefore, macrophages are an attractive target for biotechnology. Based on our hypotheses, we are developing a cell biotechnology method for creation of macrophages with a stable antitumor phenotype. We have shown that such macrophages almost doubled the survival time of mice with tumor.

  13. Durable antitumor responses to CD47 blockade require adaptive immune stimulation

    PubMed Central

    Sockolosky, Jonathan T.; Dougan, Michael; Ingram, Jessica R.; Ho, Chia Chi M.; Kauke, Monique J.; Almo, Steven C.; Ploegh, Hidde L.; Garcia, K. Christopher

    2016-01-01

    Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47–SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts. Here, we show that CD47 blockade alone or in combination with a tumor-specific antibody fails to generate antitumor immunity against syngeneic B16F10 tumors in mice. Durable tumor immunity required programmed death-ligand 1 (PD-L1) blockade in combination with an antitumor antibody, with incorporation of CD47 antagonism substantially improving response rates. Our results highlight an underappreciated contribution of the adaptive immune system to anti-CD47 adjuvant therapy and suggest that targeting both innate and adaptive immune checkpoints can potentiate the vaccinal effect of antitumor antibody therapy. PMID:27091975

  14. The innate and adaptive infiltrating immune systems as targets for breast cancer immunotherapy.

    PubMed

    Law, Andrew M K; Lim, Elgene; Ormandy, Christopher J; Gallego-Ortega, David

    2017-04-01

    A cancer cell-centric view has long dominated the field of cancer biology. Research efforts have focussed on aberrant cancer cell signalling pathways and on changes to cancer cell DNA. Mounting evidence demonstrates that many cancer-associated cell types within the tumour stroma co-evolve and support tumour growth and development, greatly modifying cancer cell behaviour, facilitating invasion and metastasis and controlling dormancy and sensitivity to drug therapy. Thus, these stromal cells represent potential targets for cancer therapy. Among these cell types, immune cells have emerged as a promising target for therapy. The adaptive and the innate immune system play an important role in normal mammary development and breast cancer. The number of infiltrating adaptive immune system cells with tumour-rejecting capacity, primarily, T lymphocytes, is lower in breast cancer compared with other cancer types, but infiltration occurs in a large proportion of cases. There is strong evidence demonstrating the importance of the immunosuppressive role of the innate immune system during breast cancer progression. A consideration of components of both the innate and the adaptive immune system is essential for the design and development of immunotherapies in breast cancer. In this review, we focus on the importance of immunosuppressive myeloid-derived suppressor cells (MDSCs) as potential targets for breast cancer therapy.

  15. Durable antitumor responses to CD47 blockade require adaptive immune stimulation.

    PubMed

    Sockolosky, Jonathan T; Dougan, Michael; Ingram, Jessica R; Ho, Chia Chi M; Kauke, Monique J; Almo, Steven C; Ploegh, Hidde L; Garcia, K Christopher

    2016-05-10

    Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47-SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts. Here, we show that CD47 blockade alone or in combination with a tumor-specific antibody fails to generate antitumor immunity against syngeneic B16F10 tumors in mice. Durable tumor immunity required programmed death-ligand 1 (PD-L1) blockade in combination with an antitumor antibody, with incorporation of CD47 antagonism substantially improving response rates. Our results highlight an underappreciated contribution of the adaptive immune system to anti-CD47 adjuvant therapy and suggest that targeting both innate and adaptive immune checkpoints can potentiate the vaccinal effect of antitumor antibody therapy.

  16. 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 ...

  17. Type B coxsackieviruses and their interactions with the innate and adaptive immune systems

    PubMed Central

    Kemball, Christopher C; Alirezaei, Mehrdad; Whitton, J Lindsay

    2011-01-01

    Coxsackieviruses are important human pathogens, and their interactions with the innate and adaptive immune systems are of particular interest. Many viruses evade some aspects of the innate response, but coxsackieviruses go a step further by actively inducing, and then exploiting, some features of the host cell response. Furthermore, while most viruses encode proteins that hinder the effector functions of adaptive immunity, coxsackieviruses and their cousins demonstrate a unique capacity to almost completely evade the attention of naive CD8+ T cells. In this article, we discuss the above phenomena, describe the current status of research in the field, and present several testable hypotheses regarding possible links between virus infection, innate immune sensing and disease. PMID:20860480

  18. 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

  19. 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

  20. Dendritic Cells in Innate and Adaptive Immune Responses against Influenza Virus

    PubMed Central

    Summerfield, Artur; McCullough, Kenneth C.

    2009-01-01

    Dendritic cells (DC) are major players in both innate and adaptive immune responses against influenza virus. These immune responses, as well as the important interface between the innate and adaptive systems, are orchestrated by specialized subsets of DC, including conventional steady-state DC, migratory DC and plasmacytoid DC. The characteristics and efficacy of the responses are dependent on the relative activity of these DC subsets, rendering DC crucial for the development of both naïve and memory immune responses. However, due to their critical role, DC also contribute to the immunopathological processes observed during acute influenza, such as that caused by the pathogenic H5N1 viruses. Therein, the role of different DC subsets in the induction of interferon type I, pro-inflammatory cytokine and chemokine responses is important for the outcome of interaction between the virus and host immune defences. The present review will present current knowledge on this area, relating to the importance of DC activity for the induction of efficacious humoral and cell-mediated immune responses. This will include the main viral elements associated with the triggering or inhibition of DC activation. Finally, the current knowledge on understanding how differences in various vaccines influence the manner of immune defence induction will be presented. PMID:21994580

  1. Mucopolysaccharide diseases: a complex interplay between neuroinflammation, microglial activation and adaptive immunity.

    PubMed

    Archer, Louise D; Langford-Smith, Kia J; Bigger, Brian W; Fildes, James E

    2014-01-01

    Mucopolysaccharide (MPS) diseases are lysosomal storage disorders (LSDs) caused by deficiencies in enzymes required for glycosaminoglycan (GAG) catabolism. Mucopolysaccharidosis I (MPS I), MPS IIIA, MPS IIIB and MPS VII are deficient in the enzymes α-L-Iduronidase, Heparan-N-Sulphatase, N-Acetylglucosaminidase and Beta-Glucuronidase, respectively. Enzyme deficiency leads to the progressive multi-systemic build-up of heparan sulphate (HS) and dermatan sulphate (DS) within cellular lysosomes, followed by cell, tissue and organ damage and in particular neurodegeneration. Clinical manifestations of MPS are well established; however as lysosomes represent vital components of immune cells, it follows that lysosomal accumulation of GAGs could affect diverse immune functions and therefore influence disease pathogenesis. Theoretically, MPS neurodegeneration and GAGs could be substantiating a threat of danger and damage to alert the immune system for cellular clearance, which due to the progressive nature of MPS storage would propagate disease pathogenesis. Innate immunity appears to have a key role in MPS; however the extent of adaptive immune involvement remains to be elucidated. The current literature suggests a complex interplay between neuroinflammation, microglial activation and adaptive immunity in MPS disease.

  2. Stimulating immune responses to fight cancer: Basic biology and mechanisms.

    PubMed

    O'Byrne, Kenneth

    2015-04-01

    Chronic inflammation is now recognized as a major cause of malignant disease. In concert with various mechanisms (including DNA instability), hypoxia and activation of inflammatory bioactive lipid pathways and pro-inflammatory cytokines open the doorway to malignant transformation and proliferation, angiogenesis, and metastasis in many cancers. A balance between stimulatory and inhibitory signals regulates the immune response to cancer. These include inhibitory checkpoints that modulate the extent and duration of the immune response and may be activated by tumor cells. This contributes to immune resistance, especially against tumor antigen-specific T-cells. Targeting these checkpoints is an evolving approach to cancer immunotherapy, designed to foster an immune response. The current focus of these trials is on the programmed cell death protein 1 (PD-1) receptor and its ligands (PD-L1, PD-L2) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Researchers have developed anti-PD-1 and anti-PDL-1 antibodies that interfere with the ligands and receptor and allow the tumor cell to be recognized and attacked by tumor-infiltrating T-cells. These are currently being studied in lung cancer. Likewise, CTLA-4 inhibitors, which have had success treating advanced melanoma, are being studied in lung cancer with encouraging results.

  3. Neuroendocrine mechanisms for immune system regulation during stress in fish.

    PubMed

    Nardocci, Gino; Navarro, Cristina; Cortés, Paula P; Imarai, Mónica; Montoya, Margarita; Valenzuela, Beatriz; Jara, Pablo; Acuña-Castillo, Claudio; Fernández, Ricardo

    2014-10-01

    In the last years, the aquaculture crops have experienced an explosive and intensive growth, because of the high demand for protein. This growth has increased fish susceptibility to diseases and subsequent death. The constant biotic and abiotic changes experienced by fish species in culture are challenges that induce physiological, endocrine and immunological responses. These changes mitigate stress effects at the cellular level to maintain homeostasis. The effects of stress on the immune system have been studied for many years. While acute stress can have beneficial effects, chronic stress inhibits the immune response in mammals and teleost fish. In response to stress, a signaling cascade is triggered by the activation of neural circuits in the central nervous system because the hypothalamus is the central modulator of stress. This leads to the production of catecholamines, corticosteroid-releasing hormone, adrenocorticotropic hormone and glucocorticoids, which are the essential neuroendocrine mediators for this activation. Because stress situations are energetically demanding, the neuroendocrine signals are involved in metabolic support and will suppress the "less important" immune function. Understanding the cellular mechanisms of the neuroendocrine regulation of immunity in fish will allow the development of new pharmaceutical strategies and therapeutics for the prevention and treatment of diseases triggered by stress at all stages of fish cultures for commercial production.

  4. 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.

  5. The Fungal Quorum-Sensing Molecule Farnesol Activates Innate Immune Cells but Suppresses Cellular Adaptive Immunity

    PubMed Central

    Leonhardt, Ines; Spielberg, Steffi; Weber, Michael; Albrecht-Eckardt, Daniela; Bläss, Markus; Claus, Ralf; Barz, Dagmar; Scherlach, Kirstin; Hertweck, Christian; Löffler, Jürgen; Hünniger, Kerstin

    2015-01-01

    ABSTRACT Farnesol, produced by the polymorphic fungus Candida albicans, is the first quorum-sensing molecule discovered in eukaryotes. Its main function is control of C. albicans filamentation, a process closely linked to pathogenesis. In this study, we analyzed the effects of farnesol on innate immune cells known to be important for fungal clearance and protective immunity. Farnesol enhanced the expression of activation markers on monocytes (CD86 and HLA-DR) and neutrophils (CD66b and CD11b) and promoted oxidative burst and the release of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α] and macrophage inflammatory protein 1 alpha [MIP-1α]). However, this activation did not result in enhanced fungal uptake or killing. Furthermore, the differentiation of monocytes to immature dendritic cells (iDC) was significantly affected by farnesol. Several markers important for maturation and antigen presentation like CD1a, CD83, CD86, and CD80 were significantly reduced in the presence of farnesol. Furthermore, farnesol modulated migrational behavior and cytokine release and impaired the ability of DC to induce T cell proliferation. Of major importance was the absence of interleukin 12 (IL-12) induction in iDC generated in the presence of farnesol. Transcriptome analyses revealed a farnesol-induced shift in effector molecule expression and a down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor during monocytes to iDC differentiation. Taken together, our data unveil the ability of farnesol to act as a virulence factor of C. albicans by influencing innate immune cells to promote inflammation and mitigating the Th1 response, which is essential for fungal clearance. PMID:25784697

  6. Neuronal Adaptive Mechanisms Underlying Intelligent Information Processing

    DTIC Science & Technology

    1982-05-01

    omuter Procram The program consists of three functional units: stimulus presentation and data collection, histogram generation and display, and benavioral...sequence for ten second trials of adaptation, conditioning, extinction, or delayed HS paradigms. Timing of stimuli can be generated • . .. -?’ _-, a’. Ah...are generated from the data and displayed four each on Mime 100 and VT105 video terminals. The histograms are averages of three trials and are

  7. 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.

  8. 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

  9. Sublingual vaccination induces mucosal and systemic adaptive immunity for protection against lung tumor challenge.

    PubMed

    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.

  10. 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.

  11. Delivering organisational adaptation through legislative mechanisms: Evidence from the Adaptation Reporting Power (Climate Change Act 2008).

    PubMed

    Jude, S R; Drew, G H; Pollard, S J T; Rocks, S A; Jenkinson, K; Lamb, R

    2017-01-01

    There is increasing recognition that organisations, particularly in key infrastructure sectors, are potentially vulnerable to climate change and extreme weather events, and require organisational responses to ensure they are resilient and adaptive. However, detailed evidence of how adaptation is facilitated, implemented and reported, particularly through legislative mechanisms is lacking. The United Kingdom Climate Change Act (2008), introduced the Adaptation Reporting Power, enabling the Government to direct so-called reporting authorities to report their climate change risks and adaptation plans. We describe the authors' unique role and experience supporting the Department for Environment, Food and Rural Affairs (Defra) during the Adaptation Reporting Power's first round. An evaluation framework, used to review the adaptation reports, is presented alongside evidence on how the process provides new insights into adaptation activities and triggered organisational change in 78% of reporting authorities, including the embedding of climate risk and adaptation issues. The role of legislative mechanisms and risk-based approaches in driving and delivering adaptation is discussed alongside future research needs, including the development of organisational maturity models to determine resilient and well adapting organisations. The Adaptation Reporting Power process provides a basis for similar initiatives in other countries, although a clear engagement strategy to ensure buy-in to the process and research on its long-term legacy, including the potential merits of voluntary approaches, is required.

  12. Autophagy in the regulation of pathogen replication and adaptive immunity

    PubMed Central

    Randow, Felix; Münz, Christian

    2012-01-01

    Autophagy is an evolutionary conserved homeostatic process by which cells deliver cytoplasmic material for degradation into lysosomes. Autophagy may have evolved as a nutrient-providing homeostatic pathway induced upon starvation, but with the acquisition of cargo-receptors autophagy has become an important cellular defence mechanism as well as a generator of antigenic peptides for MHC presentation. We propose that autophagy efficiently protects against microbes encountering the cytosolic environment accidentally, for example upon phagosomal damage, while pathogens routinely accessing the host cytosol have evolved to avoid or even benefit from autophagy. PMID:22796170

  13. Immune Mechanisms in Inflammatory and Degenerative Eye Disease

    PubMed Central

    Perez, Victor L.; Caspi, Rachel R.

    2015-01-01

    It has recently been recognized that pathology of age-associated degenerative eye diseases such as adult macular degeneration (AMD), glaucoma and diabetic retinopathy, have strong immunological underpinnings. Attempts have been made to extrapolate to age-related degenerative disease insights from inflammatory processes associated with non-infectious uveitis, but these have not yet been sufficiently informative. Here we review recent findings on the immune processes underlying uveitis and those that have been shown to contribute to AMD, discussing in this context parallels and differences between overt inflammation and para-inflammation in the eye. We propose that mechanisms associated with ocular immune privilege, in combination with paucity of age-related antigen(s) within the target tissue, dampen what could otherwise be overt inflammation and result in the para-inflammation that characterizes age-associated neurodegenerative disease. PMID:25981967

  14. Mechanisms of Tolerance Induction by Hematopoietic Chimerism: The Immune Perspective.

    PubMed

    Yolcu, Esma S; Shirwan, Haval; Askenasy, Nadir

    2017-03-01

    Hematopoietic chimerism is one of the effective approaches to induce tolerance to donor-derived tissue and organ grafts without administration of life-long immunosuppressive therapy. Although experimental efforts to develop such regimens have been ongoing for decades, substantial cumulative toxicity of combined hematopoietic and tissue transplants precludes wide clinical implementation. Tolerance is an active immunological process that includes both peripheral and central mechanisms of mutual education of coresident donor and host immune systems. The major stages include sequential suppression of early alloreactivity, establishment of hematopoietic chimerism and suppressor cells that sustain the state of tolerance, with significant mechanistic and temporal overlap along the tolerization process. Efforts to devise less toxic transplant strategies by reduction of preparatory conditioning focus on modulation rather than deletion of residual host immunity and early reinstitution of regulatory subsets at the central and peripheral levels. Stem Cells Translational Medicine 2017;6:700-712.

  15. Modulation of Innate Immune Mechanisms to Enhance Leishmania Vaccine-Induced Immunity: Role of Coinhibitory Molecules

    PubMed Central

    Gannavaram, Sreenivas; Bhattacharya, Parna; Ismail, Nevien; Kaul, Amit; Singh, Rakesh; Nakhasi, Hira L.

    2016-01-01

    No licensed human vaccines are currently available against any parasitic disease including leishmaniasis. Several antileishmanial vaccine formulations have been tested in various animal models, including genetically modified live-attenuated parasite vaccines. Experimental infection studies have shown that Leishmania parasites utilize a broad range of strategies to undermine effector properties of host phagocytic cells, i.e., dendritic cells (DCs) and macrophages (MΦ). Furthermore, Leishmania parasites have evolved strategies to actively inhibit TH1 polarizing functions of DCs and to condition the infected MΦ toward anti-inflammatory/alternative/M2 phenotype. The altered phenotype of phagocytic cells is characterized by decreased production of antimicrobial reactive oxygen, nitrogen molecules, and pro-inflammatory cytokines, such as IFN-γ, IL-12, and TNF-α. These early events limit the activation of TH1-effector cells and set the stage for pathogenesis. Furthermore, this early control of innate immunity by the virulent parasites results in substantial alteration in the adaptive immunity characterized by reduced proliferation of CD4+ and CD8+ T cells and TH2-biased immunity that results in production of anti-inflammatory cytokines, such as TGF-β, and IL-10. More recent studies have also documented the induction of coinhibitory ligands, such as CTLA-4, PD-L1, CD200, and Tim-3, that induce exhaustion and/or non-proliferation in antigen-experienced T cells. Most of these studies focus on viral infections in chronic phase, thus limiting the direct application of these results to parasitic infections and much less to parasitic vaccines. However, these studies suggest that vaccine-induced protective immunity can be modulated using strategies that enhance the costimulation that might reduce the threshold necessary for T cell activation and conversely by strategies that reduce or block inhibitory molecules, such as PD-L1 and CD200. In this review, we will focus on the

  16. Platelets: versatile modifiers of innate and adaptive immune responses to transplants

    PubMed Central

    Baldwin, William M; Kuo, Hsiao-Hsuan; Morrell, Craig N

    2011-01-01

    Purpose of review Over the last decade, there has been mounting experimental data demonstrating that platelets contribute to acute vascular inflammation and atherosclerosis. This review focuses on recent findings that link platelets to inflammatory responses of relevance to transplants. Recent findings Although it has been known that platelets modify vascular inflammation by secretion of soluble mediators and release of microparticles, new aspects of these mechanisms are being defined. For example, platelet-derived RANTES (CCL5) not only functions in homomers, but also forms more potent heteromers with Platelet Factor 4 (CXCL4). This heteromer formation can be inhibited with small molecules. New findings also demonstrate heterologous interactions of platelet microparticles with leukocytes that may increase their range of impact. By attaching to neutrophils, platelet microparticles appear to migrate out of blood vessels and into other compartments where they stimulate secretion of cytokines. Contact of platelets with extracellular matrix also can result in cleavage of hyaluronan into fragments that serve as an endogenous danger signal. Summary Recent findings have expanded the range of interactions by which platelets can modify innate and adaptive immune responses to transplants. PMID:21157344

  17. 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.

  18. T cell intrinsic roles of autophagy in promoting adaptive immunity

    PubMed Central

    Walsh, Craig M.; Bell, Bryan D.

    2010-01-01

    Autophagy, an ancient cellular response where autophagic vacuoles are formed within the cytosol, is induced in response to a variety of cellular insults, including growth factor or nutrient withdrawal, organelle damage and misfolded proteins. Autophagy is rapidly induced in T lymphocytes following antigenic stimulation and blockade of autophagic signaling greatly reduces T cell clonal expansion, suggesting that autophagy is primarily involved in promoting T cell survival. In contrast, a recently identified negative feedback loop involving FADD and caspase-8, limits the level of autophagy in T cells. Failure to activate caspase-8 during T cell mitogenesis leads to hyperactive autophagy and cellular death through a programmed necrotic mechanism. These findings suggest that crosstalk between these cellular processes is essential for T cell activation and homeostasis. PMID:20392618

  19. Adaptive Finite-Element Computation In Fracture Mechanics

    NASA Technical Reports Server (NTRS)

    Min, J. B.; Bass, J. M.; Spradley, L. W.

    1995-01-01

    Report discusses recent progress in use of solution-adaptive finite-element computational methods to solve two-dimensional problems in linear elastic fracture mechanics. Method also shown extensible to three-dimensional problems.

  20. Prostate cancer stem cells are targets of both innate and adaptive immunity and elicit tumor-specific immune responses

    PubMed Central

    Jachetti, Elena; Mazzoleni, Stefania; Grioni, Matteo; Ricupito, Alessia; Brambillasca, Chiara; Generoso, Luca; Calcinotto, Arianna; Freschi, Massimo; Mondino, Anna; Galli, Rossella; Bellone, Matteo

    2013-01-01

    According to the cancer stem cell (CSC) theory, therapies that do not target the CSC compartment have limited, if any, chances to eradicate established tumors. While cytotoxic T lymphocytes (CTLs) have the potential to recognize and kill single neoplastic cells within a tissue, whether CSCs can be targeted by the immune system during spontaneous or vaccination-elicited responses is poorly defined. Here, we provide experimental evidence showing that CSC lines established from the prostate of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice expressed prostate cancer-associated antigens, MHC Class I and II molecules as well as ligands for natural killer (NK) cell receptors. Indeed, CSC were targets for both NK cell- and CTL-mediated cytotoxicity, both in vitro and in vivo. The administration of dendritic cells pulsed with irradiated CSCs induced a tumor-specific immune response that was more robust than that induced by dendritic cells pulsed with differentiated tumor cells, delayed tumor growth in mice challenged with prostate CSCs and caused tumor regression in TRAMP mice. Thus, CSC are targeted by both innate and adaptive immune responses and might be exploited for the design of novel immunotherapeutic approaches against cancer. PMID:23762811

  1. 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

  2. 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

  3. Adaptive innate immunity? Responsive-mode prophylaxis in the mealworm beetle, Tenebrio molitor.

    PubMed Central

    Moret, Yannick; Siva-Jothy, Michael T

    2003-01-01

    A primary infection by a parasite may indicate a higher risk of being reinfected in the near future (since infection may indicate that enemies are becoming more abundant). Acquired immunity does not exist in invertebrates despite the fact that they also face increased risks of reinfection following primary exposure. However, when subjected to immune insult, insects can produce immune responses that persist for long enough to provide prophylaxis. Because these immune responses are costly, persistence must be maintained through a selective advantage. We tested for the possibility that these long-lasting immune responses provided increased resistance to later infections by experimentally mimicking a primary immune insult (pre-challenge) in larvae of the mealworm beetle, Tenebrio molitor, with lipopolysaccharides (LPS) prior to early or late exposure to spores of the entomopathogenic fungus Metarhizium anisopliae. We found that pre-challenged larvae produced a long-lasting antimicrobial response, which provided a survival benefit when the larvae were exposed to fungal infection. These results suggest that the observed response is functionally "adaptive". PMID:14667338

  4. Mechanisms Of Hypoxia-Induced Immune Escape In Cancer And Their Regulation By Nitric Oxide.

    PubMed

    Graham, Charles; Barsoum, Ivraym; Kim, Judy; Black, Madison; Siemens, Robert D

    2015-08-01

    The acquired ability of tumour cells to avoid destruction by immune effector mechanisms (immune escape) is important for malignant progression. Also associated with malignant progression is tumour hypoxia, which induces aggressive phenotypes such as invasion, metastasis and drug resistance in cancer cells. Our studies revealed that hypoxia contributes to escape from innate immunity by increasing tumour cell expression of the metalloproteinase ADAM10 in a manner dependent on accumulation of the alpha subunit of the transcription factor hypoxia-inducible factor-1 (HIF-1α). Increased ADAM10 expression leads to shedding of the NK cell-activating ligand, MICA, from the surface of tumour cells, thereby resulting in resistance to NK cell-mediated lysis. Our more recent studies demonstrated that hypoxia, also via HIF-1α accumulation, increases the expression of the inhibitory co-stimulatory ligand PD-L1 on tumour cells. Elevated PD-L1 expression leads to escape from adaptive immunity via increased apoptosis of CD8(+) cytotoxic T lymphocytes. Accumulating evidence indicates that hypoxia-induced acquisition of malignant phenotypes, including immune escape, is in part due to impaired nitric oxide (NO)-mediated activation of cGMP signalling and that restoration of cGMP signalling prevents such hypoxic responses. We have shown that NO/cGMP signalling inhibits hypoxia-induced malignant phenotypes likely in part by interfering with HIF-1α accumulation via a mechanism involving calpain. These findings indicate that activation of NO/cGMP signalling may have useful applications in cancer therapy.

  5. Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes

    PubMed Central

    Ku, Amy W; Muhitch, Jason B; Powers, Colin A; Diehl, Michael; Kim, Minhyung; Fisher, Daniel T; Sharda, Anand P; Clements, Virginia K; O'Loughlin, Kieran; Minderman, Hans; Messmer, Michelle N; Ma, Jing; Skitzki, Joseph J; Steeber, Douglas A; Walcheck, Bruce; Ostrand-Rosenberg, Suzanne; Abrams, Scott I; Evans, Sharon S

    2016-01-01

    Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive network that drives cancer escape by disabling T cell adaptive immunity. The prevailing view is that MDSC-mediated immunosuppression is restricted to tissues where MDSC co-mingle with T cells. Here we show that splenic or, unexpectedly, blood-borne MDSC execute far-reaching immune suppression by reducing expression of the L-selectin lymph node (LN) homing receptor on naïve T and B cells. MDSC-induced L-selectin loss occurs through a contact-dependent, post-transcriptional mechanism that is independent of the major L-selectin sheddase, ADAM17, but results in significant elevation of circulating L-selectin in tumor-bearing mice. Even moderate deficits in L-selectin expression disrupt T cell trafficking to distant LN. Furthermore, T cells preconditioned by MDSC have diminished responses to subsequent antigen exposure, which in conjunction with reduced trafficking, severely restricts antigen-driven expansion in widely-dispersed LN. These results establish novel mechanisms for MDSC-mediated immunosuppression that have unanticipated implications for systemic cancer immunity. DOI: http://dx.doi.org/10.7554/eLife.17375.001 PMID:27929373

  6. 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.

  7. Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes.

    PubMed

    Ku, Amy W; Muhitch, Jason B; Powers, Colin A; Diehl, Michael; Kim, Minhyung; Fisher, Daniel T; Sharda, Anand P; Clements, Virginia K; O'Loughlin, Kieran; Minderman, Hans; Messmer, Michelle N; Ma, Jing; Skitzki, Joseph J; Steeber, Douglas A; Walcheck, Bruce; Ostrand-Rosenberg, Suzanne; Abrams, Scott I; Evans, Sharon S

    2016-12-08

    Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive network that drives cancer escape by disabling T cell adaptive immunity. The prevailing view is that MDSC-mediated immunosuppression is restricted to tissues where MDSC co-mingle with T cells. Here we show that splenic or, unexpectedly, blood-borne MDSC execute far-reaching immune suppression by reducing expression of the L-selectin lymph node (LN) homing receptor on naïve T and B cells. MDSC-induced L-selectin loss occurs through a contact-dependent, post-transcriptional mechanism that is independent of the major L-selectin sheddase, ADAM17, but results in significant elevation of circulating L-selectin in tumor-bearing mice. Even moderate deficits in L-selectin expression disrupt T cell trafficking to distant LN. Furthermore, T cells preconditioned by MDSC have diminished responses to subsequent antigen exposure, which in conjunction with reduced trafficking, severely restricts antigen-driven expansion in widely-dispersed LN. These results establish novel mechanisms for MDSC-mediated immunosuppression that have unanticipated implications for systemic cancer immunity.

  8. 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.

  9. A Perspective on Roles Played by Innate and Adaptive Immunity in the Pathobiology of Neurodegenerative Disorders

    PubMed Central

    Gendelman, Howard E.; Mosley, R. Lee

    2015-01-01

    Aberrant innate and adaptive immune responses are neurodegenerative disease effectors. Disease is heralded by a generalized but subtle immune activation orchestrated by the release of extracellular prion-like aggregated and oxidized or otherwise modified proteins. These are responsible for an inflammatory neurotoxic cascade. The perpetrators of such events include effector T cells and activated microglia. What ensues are Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis and stroke with changed frequencies of effector T cell and reduced numbers or function of regulatory lymphocytes. The control of such immune responses could lead to new therapeutic strategies and the means to effectively combat a composite of diseases that have quite limited therapeutic options. PMID:26520433

  10. An Overview of the Innate and Adaptive Immune System in Inflammatory Bowel Disease.

    PubMed

    Choy, Matthew C; Visvanathan, Kumar; De Cruz, Peter

    2017-01-01

    Inflammatory bowel diseases (IBDs) are thought to develop as a result of complex interactions between host genetics, the immune system and the environment including the gut microbiome. Although an improved knowledge of the immunopathogenesis of IBDs has led to great advances in therapy such as the highly effective anti-tumor necrosis factor class of medications, a significant proportion of patients with Crohn's disease and ulcerative colitis do not respond to anti-tumor necrosis factor antibodies. Further understanding of the different immune pathways involved in the genesis of chronic intestinal inflammation is required to help find effective treatments for IBDs. In this review, the role of the mucosal innate and adaptive immune system in IBD is summarized, highlighting new areas of discovery which may hold the key to identifying novel predictive or prognostic biomarkers and new avenues of therapeutic discovery.

  11. Role Of Immature Myeloid Cells in Mechanisms of Immune Evasion In Cancer1

    PubMed Central

    Kusmartsev, Sergei; Gabrilovich, Dmitry I.

    2005-01-01

    Tumor affects myelopoiesis by inhibiting the process of differentiation/maturation of antigen-presenting cells from their myeloid precursors and by stimulating an accumulation of immature myeloid cells in cancer patients and tumor-bearing mice. These immature myeloid cells can contribute greatly to tumor progression and promote tumor evasion from immune attack: i) by inhibiting development of adaptive immune responses against tumor in lymphoid organs; ii) by migrating into tumor site and differentiating there into highly immune suppressive tumor-associated macrophages. Immature myeloid cells and tumor-associated macrophages utilize different JAK/STAT signaling pathways and different mechanisms to control T cell responses, which include increased production of TGF-beta, reactive oxygen species, peroxynitrites, as well as enhanced L-arginine metabolism. Understanding of precise mechanisms, which tumors use to affect differentiation of APC from myeloid cell precursors and inhibit T cell responses, could help to develop new approaches for cancer therapy and substantially improve efficiency of existing cancer vaccination strategies. PMID:16047143

  12. Role of immature myeloid cells in mechanisms of immune evasion in cancer.

    PubMed

    Kusmartsev, Sergei; Gabrilovich, Dmitry I

    2006-03-01

    Tumor affects myelopoiesis by inhibiting the process of differentiation/maturation of antigen-presenting cells from their myeloid precursors and by stimulating an accumulation of immature myeloid cells in cancer patients and tumor-bearing mice. These immature myeloid cells can contribute greatly to tumor progression and promote tumor evasion from immune attack: i) by inhibiting development of adaptive immune responses against tumor in lymphoid organs; ii) by migrating into tumor site and differentiating there into highly immune suppressive tumor-associated macrophages. Immature myeloid cells and tumor-associated macrophages utilize different JAK/STAT signaling pathways and different mechanisms to control T cell responses, which include increased production of TGF-beta, reactive oxygen species, peroxynitrites, as well as enhanced L-arginine metabolism. Understanding of precise mechanisms, which tumors use to affect differentiation of APC from myeloid cell precursors and inhibit T cell responses, could help to develop new approaches for cancer therapy and substantially improve efficiency of existing cancer vaccination strategies.

  13. A synaptic mechanism for retinal adaptation to luminance and contrast

    PubMed Central

    Jarsky, Tim; Cembrowski, Mark; Logan, Stephen M.; Kath, William L.; Riecke, Hermann; Demb, Jonathan B.; Singer, Joshua H.

    2011-01-01

    The gain of signaling in primary sensory circuits is matched to the stimulus intensity by the process of adaptation. Retinal neural circuits adapt to visual scene statistics, including the mean (background adaptation) and the temporal variance (contrast adaptation) of the light stimulus. The intrinsic properties of retinal bipolar cells and synapses contribute to background and contrast adaptation, but it is unclear whether both forms of adaptation depend on the same cellular mechanisms. Studies of bipolar cell synapses identified synaptic mechanisms of gain control, but the relevance of these mechanisms to visual processing is uncertain owing to the historical focus on fast, phasic transmission rather than the tonic transmission evoked by ambient light. Here, we studied use-dependent regulation of bipolar cell synaptic transmission evoked by small, ongoing modulations of membrane potential (VM) in the physiological range. We made paired whole-cell recordings from rod bipolar (RB) and AII amacrine cells in a mouse retinal slice preparation. Quasi-white noise voltage commands modulated RB VM and evoked EPSCs in the AII. We mimicked changes in background luminance or contrast, respectively, by depolarizing the VM or increasing its variance. A linear systems analysis of synaptic transmission showed that increasing either the mean or the variance of the presynaptic VM reduced gain. Further electrophysiological and computational analyses demonstrated that adaptation to mean potential resulted from both Ca channel inactivation and vesicle depletion, whereas adaptation to variance resulted from vesicle depletion alone. Thus, background and contrast adaptation apparently depend in part on a common synaptic mechanism. PMID:21795549

  14. Effects of stress associated with weaning on the adaptive immune system in pigs.

    PubMed

    Kick, A R; Tompkins, M B; Flowers, W L; Whisnant, C S; Almond, G W

    2012-02-01

    This study was designed to investigate the effects of weaning age on specific components of the adaptive immune system in pigs. Twenty-three crossbred pigs were randomly assigned to 1 of 3 treatments: weaning at 14 (14D, n = 8), 21 (21D, n = 7), or 28 (28D, n = 8) d of age. Peripheral blood samples, obtained when pigs were 13, 15, 20, 22, 27, 29, and 35 d of age, were analyzed for peripheral blood cell percentages and concentrations of neutrophils, lymphocytes, T cell subsets, mature B cells, and plasma cortisol concentrations. For each of the 3 groups, weaning increased plasma cortisol concentrations (P < 0.001) and reduced BW percentage change (P < 0.017). Lymphocyte concentrations displayed a treatment effect for the 14D (P = 0.074) and 28D (P = 0.014) groups. Albeit inconsistent, lymphocyte concentrations were less in weaned pigs on the day after weaning than in pigs remaining on the sow or weaned at a younger age. Specifically, mature B cells (CD21(+)) and CD4(+)CD8(+) cells decreased (P < 0.05) after weaning at 28 d of age. Other differences occurred among treatments; however, the differences apparently were not associated with weaning. Based upon the immunological measures used in the present study, there was not an explicit benefit to the adaptive immune system for any weaning age. Early weaning did not negatively affect the adaptive immunological competence of pigs as determined by changes in populations of immune cells.

  15. Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease.

    PubMed

    Allen Reish, Heather E; Standaert, David G

    2015-01-01

    Alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson disease (PD). Gene duplications, triplications and point mutations in SNCA1, the gene encoding α-syn, cause autosomal dominant forms of PD. Aggregated and post-translationally modified forms of α-syn are present in Lewy bodies and Lewy neurites in both sporadic and familial PD, and recent work has emphasized the prion-like ability of aggregated α-syn to produce spreading pathology. Accumulation of abnormal forms of α-syn is a trigger for PD, but recent evidence suggests that much of the downstream neurodegeneration may result from inflammatory responses. Components of both the innate and adaptive immune systems are activated in PD, and influencing interactions between innate and adaptive immune components has been shown to modify the pathological process in animal models of PD. Understanding the relationship between α-syn and subsequent inflammation may reveal novel targets for neuroprotective interventions. In this review, we examine the role of α-syn and modified forms of this protein in the initiation of innate and adaptive immune responses.

  16. Mechanisms underlying neglect recovery after prism adaptation.

    PubMed

    Serino, Andrea; Angeli, Valentina; Frassinetti, Francesca; Làdavas, Elisabetta

    2006-01-01

    Prism adaptation (PA) has been demonstrated to be effective in improving hemispatial neglect. However not all patients seem to benefit from this procedure. Thus, the objective of the present work is to provide behavioural and neuroanatomical predictors of recovery by exploring the reorganization of low-order visuo-motor behaviour and high-order visuo-spatial representation induced by PA. To this end, 16 neglect patients (experimental group) were submitted to a PA treatment for 10 daily sessions. Neglect and oculo-motor responses were assessed before the treatment, 1 week, 1 and 3 months after the treatment. Eight control patients, who received general cognitive stimulation, were submitted to the same tests at the same time interval. The results showed that experimental patients obtained, as a consequence of PA, a long lasting neglect recovery, a reorganization of low-order visuo-motor behaviour during and after prism exposure (error reduction and after-effect, respectively) and a leftward deviation of oculo-motor responses. Importantly, the level of error reduction obtained in the first week of treatment was predictive of neglect recovery and the amelioration of oculo-motor responses, and the degree of eye movement deviation was positively related to neglect amelioration. Finally, the study of patients' neuroanatomical data showed that severe occipital lesions were associated with a lack of error reduction, poor neglect recovery and reduced oculo-motor system amelioration. In conclusion, the present results suggest that low-order visuo-motor reorganization induced by PA promotes a resetting of the oculo-motor system leading to an improvement in high-order visuo-spatial representation able to ameliorate neglect.

  17. Stimuli-Responsive Mechanically Adaptive Polymer Nanocomposites

    PubMed Central

    Shanmuganathan, Kadhiravan; Capadona, Jeffrey R.; Rowan, Stuart J.; Weder, Christoph

    2010-01-01

    A new series of biomimetic stimuli-responsive nanocomposites, which change their mechanical properties upon exposure to physiological conditions, was prepared and investigated. The materials were produced by introducing percolating networks of cellulose nanofibers or “whiskers” derived from tunicates into poly(vinyl acetate) (PVAc), poly(butyl methacrylate) (PBMA), and blends of these polymers, with the objective of determining how the hydrophobicity and glass-transition temperature (Tg) of the polymer matrix affect the water-induced mechanically dynamic behavior. Below the Tg (~60–70 °C), the incorporation of whiskers (15.1 – 16.5% v/v) modestly increased the tensile storage moduli (E′) of the neat polymers from 0.6 to 3.8 GPa (PBMA) and from 2 to 5.2 GPa (PVAc). The reinforcement was much more dramatic above Tg, where E′ increased from 1.2 to 690 MPa (PVAc) and ~1 to 1.1 GPa (PBMA). Upon exposure to physiological conditions (immersion in artificial cerebrospinal fluid, ACSF, at 37 °C) all materials displayed a decrease of E′. The most significant contrast was seen in PVAc; for example the E′ of a 16.5% v/v PVAc/whisker nanocomposite decreased from 5.2 GPa to 12.7 MPa. Only a modest modulus decrease was measured for PBMA/whisker nanocomposite; here the E′ of a 15.1% v/v PBMA/whisker nanocomposite decreased from 3.8 to 1.2 GPa. A systematic investigation revealed that the magnitude of the mechanical contrast was related to the degree of swelling with ACSF, which was shown to increase with whisker content, temperature, and polarity of the matrix (PVAc > PBMA). The mechanical morphing of the new materials can be described in the framework of both the percolation and Halpin-Kardos models for nanocomposite reinforcement, and is the result of changing interactions among the nanoparticles and plasticization of the matrix upon swelling. PMID:20305827

  18. Immunological mechanisms of adaptation to the low-weight chemical compounds in ontogenesis.

    PubMed

    Glushkov, A N

    2003-09-01

    It is postulated that adaptation to the low-weight chemical compounds includes six consistent ontogenetic periods: the reciprocal selection of the marriage partners; the maturation of the gametes; the formation of the zygote; the development of the fetus; the birth and nursing of the child; and the sexual maturation of a human being. The main immunological parts of adaptation are: the antibodies to the low-weight xeno- and endobiotics; the reciprocal immune-like recognition of the maternal and paternal gametes; and the maternal immune reaction on the paternal histocompatibility antigens of the fetus. The main immunological mechanisms of adaptation are: the promotion of the selectivity in the smell recognition of the marriage partners by the antibodies to the xeno- and endobiotics expanding the individual spectrum of their metabolites; the inhibition of the xenobiotic genotoxic action on the gametes, fetus and child by the antibodies; the prevention of the development of gene-damaged gametes and fetus by antibodies to the sexual hormones; and the immune preservation (elimination) of the heterozygote (homozygote) fetus.

  19. Adaptive immune response to lipoproteins of Staphylococcus aureus in healthy subjects

    PubMed Central

    Vu, Chi Hai; Kolata, Julia; Stentzel, Sebastian; Beyer, Anica; Gesell Salazar, Manuela; Steil, Leif; Pané‐Farré, Jan; Rühmling, Vanessa; Engelmann, Susanne; Götz, Friedrich; van Dijl, Jan Maarten; Hecker, Michael; Mäder, Ulrike; Schmidt, Frank; Völker, Uwe

    2016-01-01

    Staphylococcus aureus is a frequent commensal but also a dangerous pathogen, causing many forms of infection ranging from mild to life‐threatening conditions. Among its virulence factors are lipoproteins, which are anchored in the bacterial cell membrane. Lipoproteins perform various functions in colonization, immune evasion, and immunomodulation. These proteins are potent activators of innate immune receptors termed Toll‐like receptors 2 and 6. This study addressed the specific B‐cell and T‐cell responses directed to lipoproteins in human S. aureus carriers and non‐carriers. 2D immune proteomics and ELISA approaches revealed that titers of antibodies (IgG) binding to S. aureus lipoproteins were very low. Proliferation assays and cytokine profiling data showed only subtle responses of T cells; some lipoproteins did not elicit proliferation. Hence, the robust activation of the innate immune system by S. aureus lipoproteins does not translate into a strong adaptive immune response. Reasons for this may include inaccessibility of lipoproteins for B cells as well as ineffective processing and presentation of the antigens to T cells. PMID:27324828

  20. Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment

    PubMed Central

    Starobinets, Hanna; Ye, Jordan; Broz, Miranda; Barry, Kevin; Goldsmith, Juliet; Marsh, Timothy; Rostker, Fanya

    2016-01-01

    The rising success of cancer immunotherapy has produced immense interest in defining the clinical contexts that may benefit from this therapeutic approach. To this end, there is a need to ascertain how the therapeutic modulation of intrinsic cancer cell programs influences the anticancer immune response. For example, the role of autophagy as a tumor cell survival and metabolic fitness pathway is being therapeutically targeted in ongoing clinical trials that combine cancer therapies with antimalarial drugs for the treatment of a broad spectrum of cancers, many of which will likely benefit from immunotherapy. However, our current understanding of the interplay between autophagy and the immune response remains incomplete. Here, we have evaluated how autophagy inhibition impacts the antitumor immune response in immune-competent mouse models of melanoma and mammary cancer. We observed equivalent levels of T cell infiltration and function within autophagy-competent and -deficient tumors, even upon treatment with the anthracycline chemotherapeutic doxorubicin. Similarly, we found equivalent T cell responses upon systemic treatment of tumor-bearing mice with antimalarial drugs. Our findings demonstrate that antitumor adaptive immunity is not adversely impaired by autophagy inhibition in these models, allowing for the future possibility of combining autophagy inhibitors with immunotherapy in certain clinical contexts. PMID:27775547

  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. Intestinal Epithelial Cell Regulation of Adaptive Immune Dysfunction in Human Type 1 Diabetes

    PubMed Central

    Graves, Christina L.; Li, Jian; LaPato, Melissa; Shapiro, Melanie R.; Glover, Sarah C.; Wallet, Mark A.; Wallet, Shannon M.

    2017-01-01

    Environmental factors contribute to the initiation, progression, and maintenance of type 1 diabetes (T1D), although a single environmental trigger for disease has not been identified. Studies have documented the contribution of immunity within the gastrointestinal tract (GI) to the expression of autoimmunity at distal sites. Intestinal epithelial cells (IECs) regulate local and systemic immunologic homeostasis through physical and biochemical interactions with innate and adaptive immune populations. We hypothesize that a loss in the tolerance-inducing nature of the GI tract occurs within T1D and is due to altered IECs’ innate immune function. As a first step in addressing this hypothesis, we contrasted the global immune microenvironment within the GI tract of individuals with T1D as well as evaluated the IEC-specific effects on adaptive immune cell phenotypes. The soluble and cellular immune microenvironment within the duodenum, the soluble mediator profile of primary IECs derived from the same duodenal tissues, and the effect of the primary IECs’ soluble mediator profile on T-cell expansion and polarization were evaluated. Higher levels of IL-17C and beta-defensin 2 (BD-2) mRNA in the T1D-duodenum were observed. Higher frequencies of type 1 innate lymphoid cells (ILC1) and CD8+CXCR3+ T-cells (Tc1) were also observed in T1D-duodenal tissues, concomitant with lower frequencies of type 3 ILC (ILC3) and CD8+CCR6+ T-cells (Tc17). Higher levels of proinflammatory mediators (IL-17C and BD-2) in the absence of similar changes in mediators associated with homeostasis (interleukin 10 and thymic stromal lymphopoietin) were also observed in T1D-derived primary IEC cultures. T1D-derived IEC culture supernatants induced more robust CD8+ T-cell proliferation along with enhanced polarization of Tc1 populations, at the expense of Tc17 polarization, as well as the expansion of CXCR3+CCR6+/− Tregs, indicative of a Th1-like and less regulatory phenotype. These data demonstrate

  3. Oral exposure of broiler breeder hens to extra thyroxine modulates early adaptive immune responses in progeny chicks.

    PubMed

    Akhlaghi, A; Zamiri, M J; Jafari Ahangari, Y; Atashi, H; Ansari Pirsaraei, Z; Deldar, H; Eghbalian, A N; Akhlaghi, A A; Navidshad, B; Yussefi Kelarikolaei, K; Hashemi, S R

    2013-04-01

    Based on the findings of a recent study suggesting a decreased cold-induced ascites incidence in broiler progeny from hyperthyroid (HYPER) breeder hens, and a controversy on the effects of hyperthyroidism on immunocompetence, the present study was conducted to determine the probable adverse effect of induced maternal hyperthyroidism on immune function in progeny chicks. Breeder hens (n = 88) were randomly allotted to the control or HYPER groups and received common or thyroxine (T4)-added (1 mg/L) water, respectively. The hens were artificially inseminated, and hatching eggs (n = 924) were incubated. Thereafter, the male hatchlings (n = 288) were reared for 42 d, and several cellular and humoral immune responses were evaluated at standard or low ambient temperature. Prevaccination antibody titers to Newcastle disease, infectious bronchitis, and infectious bursal disease virus were higher in HYPER chicks during 1 wk of age, although not different in their dams. For primary response to SRBC administered at 7 d of age, HYPER chicks recorded higher total, IgM (d 14), and IgG (d 21) anti-SRBC antibody titers. Higher cutaneous basophilic hypersensitivity response in HYPER chicks (d 10) was not observed at 35 d of age. Carbon clearance assay showed no difference, but in vitro lymphoproliferative response to concanavalin A was higher in 19-d-old HYPER chicks, independent of temperature treatment. An increase in lymphocyte percentage coincided with a decreased heterophil percentage and heterophil to lymphocyte ratio (d 14) in the HYPER group. The weight of lymphoid organs in progeny was not influenced by the oral exposure of dams to extra T4. Independent of T4 treatment, cold exposure was generally associated with decreased immune functions at early stages. The data suggested that oral exposure of broiler breeder hens to 1 mg/L of T4 not only had no adverse effect on immune function, but also modulated early adaptive immune responses in progeny chicks for which the causal

  4. Pressure Induced Changes in Adaptive Immune Function in Belugas (Delphinapterus leucas); Implications for Dive Physiology and Health.

    PubMed

    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

  5. 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

  6. Microwear, mechanics and the feeding adaptations of Australopithecus africanus.

    PubMed

    Strait, David S; Weber, Gerhard W; Constantino, Paul; Lucas, Peter W; Richmond, Brian G; Spencer, Mark A; Dechow, Paul C; Ross, Callum F; Grosse, Ian R; Wright, Barth W; Wood, Bernard A; Wang, Qian; Byron, Craig; Slice, Dennis E

    2012-01-01

    Recent studies of dental microwear and craniofacial mechanics have yielded contradictory interpretations regarding the feeding ecology and adaptations of Australopithecus africanus. As part of this debate, the methods used in the mechanical studies have been criticized. In particular, it has been claimed that finite element analysis has been poorly applied to this research question. This paper responds to some of these mechanical criticisms, highlights limitations of dental microwear analysis, and identifies avenues of future research.

  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

    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.

  9. 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

  10. Paraventricular Hypothalamic Mechanisms of Chronic Stress Adaptation

    PubMed Central

    Herman, James P.; Tasker, Jeffrey G.

    2016-01-01

    The hypothalamic paraventricular nucleus (PVN) is the primary driver of hypothalamo–pituitary–adrenocortical (HPA) responses. At least part of the role of the PVN is managing the demands of chronic stress exposure. With repeated exposure to stress, hypophysiotrophic corticotropin-releasing hormone (CRH) neurons of the PVN display a remarkable cellular, synaptic, and connectional plasticity that serves to maximize the ability of the HPA axis to maintain response vigor and flexibility. At the cellular level, chronic stress enhances the production of CRH and its co-secretagogue arginine vasopressin and rearranges neurotransmitter receptor expression so as to maximize cellular excitability. There is also evidence to suggest that efficacy of local glucocorticoid feedback is reduced following chronic stress. At the level of the synapse, chronic stress enhances cellular excitability and reduces inhibitory tone. Finally, chronic stress causes a structural enhancement of excitatory innervation, increasing the density of glutamate and noradrenergic/adrenergic terminals on CRH neuronal cell somata and dendrites. Together, these neuroplastic changes favor the ability of the HPA axis to retain responsiveness even under conditions of considerable adversity. Thus, chronic stress appears able to drive PVN neurons via a number of convergent mechanisms, processes that may play a major role in HPA axis dysfunction seen in variety of stress-linked disease states. PMID:27843437

  11. Seminal fluid and immune adaptation for pregnancy--comparative biology in mammalian species.

    PubMed

    Schjenken, J E; Robertson, S A

    2014-09-01

    Seminal fluid delivered to the female reproductive tract at coitus not only promotes the survival and fertilizing capacity of spermatozoa, but also contains potent signalling agents that influence female reproductive physiology to improve the chances of conception and reproductive success. Male to female seminal fluid signalling occurs in rodents, domestic and livestock animals, and all other mammals examined to date. Seminal plasma is instrumental in eliciting the female response, by provision of cytokines and prostaglandins synthesized in the male accessory glands. These agents bind to receptors on target cells in the cervix and uterus, activating changes in gene expression leading to functional adaptations in the female tissues. Sperm also interact with female tract cells, although the molecular basis of this interaction is not yet defined. The consequences are increased sperm survival and fertilization rates, conditioning of the female immune response to tolerate semen and the conceptus, and molecular and cellular changes in the endometrium that facilitate embryo development and implantation. Studies in porcine, equine, bovine, ovine and canine species all show evidence of male-female signalling function for seminal fluid. There are variations between species that relate to their different reproductive strategies and behaviours, particularly the site of seminal fluid deposition and female reproductive tract anatomy. Although the details of the molecular mechanisms require more study, the available data are consistent with both the sperm and plasma fractions of seminal fluid acting in a synergistic fashion to activate inflammation-like responses and downstream female tract changes in each of these species. Insight into the biological function and molecular basis of seminal fluid signalling in the female will inform new interventions and management practices to support optimal reproductive outcomes in domestic, livestock and endangered animal species.

  12. Mechanisms and pathways of innate immune activation and regulation in health and cancer

    PubMed Central

    Cui, Jun; Chen, Yongjun; Wang, Helen Y; Wang, Rong-Fu

    2015-01-01

    Research on innate immune signaling and regulation has recently focused on pathogen recognition receptors (PRRs) and their signaling pathways. Members of PRRs sense diverse microbial invasions or danger signals, and initiate innate immune signaling pathways, leading to proinflammatory cytokines production, which, in turn, instructs adaptive immune response development. Despite the diverse functions employed by innate immune signaling to respond to a variety of different pathogens, the innate immune response must be tightly regulated. Otherwise, aberrant, uncontrolled immune responses will lead to harmful, or even fatal, consequences. Therefore, it is essential to better discern innate immune signaling and many regulators, controlling various signaling pathways, have been identified. In this review, we focus on the recent advances in our understanding of the activation and regulation of innate immune signaling in the host response to pathogens and cancer. PMID:25625930

  13. Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

    PubMed Central

    Zufferey, Anne; Kapur, Rick; Semple, John W.

    2017-01-01

    Immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by low platelet counts. The pathogenesis of ITP remains unclear although both antibody-mediated and/or T cell-mediated platelet destruction are key processes. In addition, impairment of T cells, cytokine imbalances, and the contribution of the bone marrow niche have now been recognized to be important. Treatment strategies are aimed at the restoration of platelet counts compatible with adequate hemostasis rather than achieving physiological platelet counts. The first line treatments focus on the inhibition of autoantibody production and platelet degradation, whereas second-line treatments include immunosuppressive drugs, such as Rituximab, and splenectomy. Finally, third-line treatments aim to stimulate platelet production by megakaryocytes. This review discusses the pathophysiology of ITP and how the different treatment modalities affect the pathogenic mechanisms. PMID:28208757

  14. Antimalarial Drugs as Immune Modulators: New Mechanisms for Old Drugs.

    PubMed

    An, Jie; Minie, Mark; Sasaki, Tomikazu; Woodward, Joshua J; Elkon, Keith B

    2017-01-14

    The best known of the naturally occurring antimalarial compounds are quinine, extracted from cinchona bark, and artemisinin (qinghao), extracted from Artemisia annua in China. These and other derivatives are now chemically synthesized and remain the mainstay of therapy to treat malaria. The beneficial effects of several of the antimalarial drugs (AMDs) on clinical features of autoimmune disorders were discovered by chance during World War II. In this review, we discuss the chemistry of AMDs and their mechanisms of action, emphasizing how they may impact multiple pathways of innate immunity. These pathways include Toll-like receptors and the recently described cGAS-STING pathway. Finally, we discuss the current and future impact of AMDs on systemic lupus erythematosus, rheumatoid arthritis, and devastating monogenic disorders (interferonopathies) characterized by expression of type I interferon in the brain.

  15. Porphyromonas gingivalis suppresses adaptive immunity in periodontitis, atherosclerosis, and Alzheimer's disease.

    PubMed

    Olsen, Ingar; Taubman, Martin A; Singhrao, Sim K

    2016-01-01

    Porphyromonas gingivalis, a keystone pathogen in chronic periodontitis, has been found to associate with remote body organ inflammatory pathologies, including atherosclerosis and Alzheimer's disease (AD). Although P. gingivalis has a plethora of virulence factors, much of its pathogenicity is surprisingly related to the overall immunosuppression of the host. This review focuses on P. gingivalis aiding suppression of the host's adaptive immune system involving manipulation of cellular immunological responses, specifically T cells and B cells in periodontitis and related conditions. In periodontitis, this bacterium inhibits the synthesis of IL-2 and increases humoral responses. This reduces the inflammatory responses related to T- and B-cell activation, and subsequent IFN-γ secretion by a subset of T cells. The T cells further suppress upregulation of programmed cell death-1 (PD-1)-receptor on CD(+)cells and its ligand PD-L1 on CD11b(+)-subset of T cells. IL-2 downregulates genes regulated by immune response and induces a cytokine pattern in which the Th17 lineage is favored, thereby modulating the Th17/T-regulatory cell (Treg) imbalance. The suppression of IFN-γ-stimulated release of interferon-inducible protein-10 (IP-10) chemokine ligands [ITAC (CXCL11) and Mig (CXCL9)] by P. gingivalis capsular serotypes triggers distinct T cell responses and contributes to local immune evasion by release of its outer membrane vesicles. In atherosclerosis, P. gingivalis reduces Tregs, transforms growth factor beta-1 (TGFβ-1), and causes imbalance in the Th17 lineage of the Treg population. In AD, P. gingivalis may affect the blood-brain barrier permeability and inhibit local IFN-γ response by preventing entry of immune cells into the brain. The scarcity of adaptive immune cells in AD neuropathology implies P. gingivalis infection of the brain likely causing impaired clearance of insoluble amyloid and inducing immunosuppression. By the effective manipulation of the armory of

  16. Porphyromonas gingivalis suppresses adaptive immunity in periodontitis, atherosclerosis, and Alzheimer’s disease

    PubMed Central

    Olsen, Ingar; Taubman, Martin A.; Singhrao, Sim K.

    2016-01-01

    Porphyromonas gingivalis, a keystone pathogen in chronic periodontitis, has been found to associate with remote body organ inflammatory pathologies, including atherosclerosis and Alzheimer’s disease (AD). Although P. gingivalis has a plethora of virulence factors, much of its pathogenicity is surprisingly related to the overall immunosuppression of the host. This review focuses on P. gingivalis aiding suppression of the host’s adaptive immune system involving manipulation of cellular immunological responses, specifically T cells and B cells in periodontitis and related conditions. In periodontitis, this bacterium inhibits the synthesis of IL-2 and increases humoral responses. This reduces the inflammatory responses related to T- and B-cell activation, and subsequent IFN-γ secretion by a subset of T cells. The T cells further suppress upregulation of programmed cell death-1 (PD-1)-receptor on CD+cells and its ligand PD-L1 on CD11b+-subset of T cells. IL-2 downregulates genes regulated by immune response and induces a cytokine pattern in which the Th17 lineage is favored, thereby modulating the Th17/T-regulatory cell (Treg) imbalance. The suppression of IFN-γ-stimulated release of interferon-inducible protein-10 (IP-10) chemokine ligands [ITAC (CXCL11) and Mig (CXCL9)] by P. gingivalis capsular serotypes triggers distinct T cell responses and contributes to local immune evasion by release of its outer membrane vesicles. In atherosclerosis, P. gingivalis reduces Tregs, transforms growth factor beta-1 (TGFβ-1), and causes imbalance in the Th17 lineage of the Treg population. In AD, P. gingivalis may affect the blood–brain barrier permeability and inhibit local IFN-γ response by preventing entry of immune cells into the brain. The scarcity of adaptive immune cells in AD neuropathology implies P. gingivalis infection of the brain likely causing impaired clearance of insoluble amyloid and inducing immunosuppression. By the effective manipulation of the armory of

  17. Prostate Cancer Patients Treated with Androgen Deprivation Therapy Develop Persistent Changes in Adaptive Immune Responses

    PubMed Central

    Morse, Matthew D.; McNeel, Douglas G.

    2010-01-01

    Prostate cancer is a significant cause of morbidity and mortality among men worldwide. The cornerstone treatment for metastatic prostate cancer is androgen deprivation, which has known effects on prostate tissue apoptosis and thymic regrowth. These findings, plus interest in developing immune-based treatments for prostate cancer, lead us to question whether androgen deprivation causes changes in the adaptive immune responses of prostate cancer patients, and if the timing of changes has implications for the sequencing of immunotherapies in combination with androgen deprivation. Peripheral blood mononuclear cells (PBMC) were obtained from patients prior to beginning androgen deprivation therapy (ADT) and at several time points thereafter. These cells were analyzed for the frequency of specific lymphocyte populations, and their response to stimulation. The development of prostate antigen-specific immune responses was assessed using SEREX. Patients developed expansion of the naïve T cell compartment persisting over the course of androgen deprivation, together with an increase in effector cell response to stimulation, and the generation of prostate tissue-associated IgG antibody responses, implying a potential benefit to the use of ADT in combination with prostate cancer-directed immunotherapies. The optimal timing and sequence of androgen deprivation with immune-based therapies awaits future experimental evaluation. PMID:20153396

  18. Adaptive Heterosubtypic Immunity to Low Pathogenic Avian Influenza Viruses in Experimentally Infected Mallards

    PubMed Central

    Segovia, Karen M.; Stallknecht, David E.; Kapczynski, Darrell R.; Stabler, Lisa; Berghaus, Roy D.; Fotjik, Alinde; Latorre-Margalef, Neus; França, Monique S.

    2017-01-01

    Mallards are widely recognized as reservoirs for Influenza A viruses (IAV); however, host factors that might prompt seasonality and trends in subtype diversity of IAV such as adaptive heterosubtypic immunity (HSI) are not well understood. To investigate this, we inoculated mallards with a prevailing H3N8 low pathogenic avian influenza virus (LPAIV) subtype in waterfowl to determine if prior infection with this virus would be protective against heterosubtypic infections with the H4N6, H10N7 and H14N5 LPAIV subtypes after one, two and three months, respectively. Also, we investigated the effect of cumulative immunity after sequential inoculation of mallards with these viruses in one-month intervals. Humoral immunity was assessed by microneutralization assays using a subset of representative LPAIV subtypes as antigens. Our results indicate that prior inoculation with the H3N8 virus confers partial protective immunity against subsequent heterosubtypic infections with the robustness of HSI related to the phylogenetic similarity of the HA protein of the strains used. Furthermore, induced HSI was boosted and followed by repeated exposure to more than one LPAIV subtype. Our findings provide further information on the contributions of HSI and its role in the dynamics of IAV subtype diversity in mallards. PMID:28107403

  19. Glatiramer acetate attenuates neuropathic allodynia through modulation of adaptive immune cells.

    PubMed

    Leger, Tanya; Grist, John; D'Acquisto, Fulvio; Clark, Anna K; Malcangio, Marzia

    2011-05-01

    Immune-neuronal interactions contribute to neuropathic pain. Thus, immune-competent cells such as microglia may provide targets for pain relief, as may infiltrating lymphocytes. We evaluated the nature of the lymphocyte response in the spinal cord in association with the maintenance of neuropathic allodynia. We assessed T cell contribution to pain processing by targeting these cells with Glatiramer acetate (GA) which when administered systemically reversed neuropathic allodynia, inhibited microglia response and increased IL-10 and IL-4 expressing T cells in neuropathic dorsal horns. These studies advance understanding of lymphocyte contribution to chronic pain and reveal a new mechanism of T cell intervention.

  20. Immune Responses in Neonates

    PubMed Central

    Basha, Saleem; Surendran, Naveen; Pichichero, Michael

    2015-01-01

    Neonates have little immunological memory and a developing immune system, which increases their vulnerability to infectious agents. Recent advances in understanding of neonatal immunity indicate that both innate and adaptive responses are dependent on precursor frequency of lymphocytes, antigenic dose and mode of exposure. Studies in neonatal mouse models and human umbilical cord blood cells demonstrate the capability of neonatal immune cells to produce immune responses similar to adults in some aspects but not others. This review focuses mainly on the developmental and functional mechanisms of the human neonatal immune system. In particular, the mechanism of innate and adaptive immunity and the role of neutrophils, antigen presenting cells, differences in subclasses of T lymphocytes (Th1, Th2, Tregs) and B cells are discussed. In addition, we have included the recent developments in neonatal mouse immune system. Understanding neonatal immunity is essential to development of therapeutic vaccines to combat newly emerging infectious agents. PMID:25088080

  1. 5-Lipoxygenase deficiency impairs innate and adaptive immune responses during fungal infection.

    PubMed

    Secatto, Adriana; Rodrigues, Lilian Cataldi; Serezani, Carlos Henrique; Ramos, Simone Gusmão; Dias-Baruffi, Marcelo; Faccioli, Lúcia Helena; Medeiros, Alexandra I

    2012-01-01

    5-Lipoxygenase-derived products have been implicated in both the inhibition and promotion of chronic infection. Here, we sought to investigate the roles of endogenous 5-lipoxygenase products and exogenous leukotrienes during Histoplasma capsulatum infection in vivo and in vitro. 5-LO deficiency led to increased lung CFU, decreased nitric oxide production and a deficient primary immune response during active fungal infection. Moreover, H. capsulatum-infected 5-LO(-/-) mice showed an intense influx of neutrophils and an impaired ability to generate and recruit effector T cells to the lung. The fungal susceptibility of 5-LO(-/-) mice correlated with a lower rate of macrophage ingestion of IgG-H. capsulatum relative to WT macrophages. Conversely, exogenous LTB4 and LTC4 restored macrophage phagocytosis in 5-LO deficient mice. Our results demonstrate that leukotrienes are required to control chronic fungal infection by amplifying both the innate and adaptive immune response during histoplasmosis.

  2. The B-cell antigen receptor integrates adaptive and innate immune signals

    PubMed Central

    Otipoby, Kevin L.; Waisman, Ari; Derudder, Emmanuel; Srinivasan, Lakshmi; Franklin, Andrew; Rajewsky, Klaus

    2015-01-01

    B cells respond to antigens by engagement of their B-cell antigen receptor (BCR) and of coreceptors through which signals from helper T cells or pathogen-associated molecular patterns are delivered. We show that the proliferative response of B cells to the latter stimuli is controlled by BCR-dependent activation of phosphoinositidyl 3-kinase (PI-3K) signaling. Glycogen synthase kinase 3β and Foxo1 are two PI-3K-regulated targets that play important roles, but to different extents, depending on the specific mitogen. These results suggest a model for integrating signals from the innate and the adaptive immune systems in the control of the B-cell immune response. PMID:26371314

  3. The MHC I loading complex: a multitasking machinery in adaptive immunity.

    PubMed

    Hulpke, Sabine; Tampé, Robert

    2013-08-01

    Recognition and elimination of virally or malignantly transformed cells are pivotal tasks of the adaptive immune system. For efficient immune detection, snapshots of the cellular proteome are presented as epitopes on major histocompatibility complex class I (MHC I) molecules for recognition by cytotoxic T cells. Knowledge about the track from the equivocal protein to the presentation of antigenic peptides has greatly expanded, leading to an astonishingly elaborate understanding of the MHC I peptide loading pathway. Here, we summarize the current view on this complex process, which involves ABC transporters, proteases, chaperones, and endoplasmic reticulum (ER) quality control. The contribution of individual proteins and subcomplexes is discussed, with a focus on the architecture and dynamics of the key player in the pathway, the peptide-loading complex (PLC).

  4. 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.

  5. Adaptation of the inflammatory immune response across pregnancy and postpartum in Black and White women.

    PubMed

    Gillespie, Shannon L; Porter, Kyle; Christian, Lisa M

    2016-04-01

    Pregnancy is a period of considerable physiological adaption in neuroendocrine, cardiovascular, as well as immune function. Understanding of typical changes in inflammatory immune responses during healthy pregnancy is incomplete. In addition, despite considerable racial difference in adverse pregnancy outcomes, data are lacking on potential racial differences in such adaptation. This repeated measures prospective cohort study included 37 Black and 39 White women who provided blood samples during early, mid-, and late pregnancy and 8-10 weeks postpartum. Peripheral blood mononuclear cells were incubated with lipopolysaccharide (LPS) for 24h and supernatants assayed by electrochemiluminescence to quantify interleukin(IL)-6, tumor necrosis factor(TNF)-α, IL-1β, and IL-8 production. While no changes were observed in IL-8 production over time, significant increases in IL-6, TNF-α, and IL-1β production were observed from early to late pregnancy, with subsequent declines approaching early pregnancy values at postpartum (ps<0.05). Overall, inflammatory response patterns were highly similar among Black versus White women. However, Black women had greater TNF-α production during mid-pregnancy (p=0.002) and marginally lower IL-1β production at postpartum (p=0.054). These data show a clear trajectory of change in the inflammatory immune response across pregnancy and postpartum. In this cohort of generally healthy women, Black and White women exhibited minimal differences in LPS-stimulated cytokine production across the perinatal period. Future prospective studies in Black and White women with healthy versus adverse outcomes (e.g., preeclampsia, preterm birth) would inform our understanding of the potential role of immune dysregulation in pregnant women and in relation to racial disparities in perinatal health.

  6. When Do Adaptive Developmental Mechanisms Yield Maladaptive Outcomes?

    ERIC Educational Resources Information Center

    Frankenhuis, Willem E.; Del Giudice, Marco

    2012-01-01

    This article discusses 3 ways in which adaptive developmental mechanisms may produce maladaptive outcomes. First, natural selection may favor risky strategies that enhance fitness on average but which have detrimental consequences for a subset of individuals. Second, mismatch may result when organisms experience environmental change during…

  7. Engrafted human cells generate adaptive immune responses to Mycobacterium bovis BCG infection in humanized mice

    PubMed Central

    2013-01-01

    Background Currently used mouse models fail to fully reflect human immunity to tuberculosis (TB), which hampers progress in research and vaccine development. Bone marrow-liver-thymus (BLT) mice, generated by engrafting human fetal liver, thymus, and hematopoietic stem cells in severely immunodeficient NOD/SCID/IL-2Rγ-/- (NSG) mice, have shown potential to model human immunity to infection. We engrafted HLA-A2-positive fetal tissues into NSG mice transgenically expressing human leukocyte antigen (HLA)-A2.1 (NSG-A2) to generate NSG-A2-BLT mice and characterized their human immune response to Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection to assess the utility of this model for investigating human TB. Results NSG-A2-BLT mice were infected intravenously with BCG and the immune response of engrafted human immune cells was characterized. After ex vivo antigenic stimulation of splenocytes, interferon (IFN)-γ-producing cells were detected by ELISPOT from infected, but not uninfected NSG-A2-BLT mice. However, the levels of secreted IFN-γ, determined by ELISA, were not significantly elevated by antigenic stimulation. NSG-A2-BLT mice were susceptible to BCG infection as determined by higher lung bacillary load than the non-engrafted control NSG-A2 mice. BCG-infected NSG-A2-BLT mice developed lung lesions composed mostly of human macrophages and few human CD4+ or CD8+ T cells. The lesions did not resemble granulomas typical of human TB. Conclusions Engrafted human immune cells in NSG-A2-BLT mice showed partial function of innate and adaptive immune systems culminating in antigen-specific T cell responses to mycobacterial infection. The lack of protection was associated with low IFN-γ levels and limited numbers of T cells recruited to the lesions. The NSG-A2-BLT mouse is capable of mounting a human immune response to M. tuberculosis in vivo but a quantitatively and possibly qualitatively enhanced effector response will be needed to improve the utility of this

  8. Harnessing the Prokaryotic Adaptive Immune System as a Eukaryotic Antiviral Defense.

    PubMed

    Price, Aryn A; Grakoui, Arash; Weiss, David S

    2016-04-01

    Clustered, regularly interspaced, short palindromic repeats - CRISPR-associated (CRISPR-Cas) systems - are sequence-specific RNA-directed endonuclease complexes that bind and cleave nucleic acids. These systems evolved within prokaryotes as adaptive immune defenses to target and degrade nucleic acids derived from bacteriophages and other foreign genetic elements. The antiviral function of these systems has now been exploited to combat eukaryotic viruses throughout the viral life cycle. Here we discuss current advances in CRISPR-Cas9 technology as a eukaryotic antiviral defense.

  9. Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system.

    PubMed

    Flajnik, M F; Kasahara, M

    2001-09-01

    MHC gene organization (size, complexity, gene order) differs markedly among different species, and yet all nonmammalian vertebrates examined to date have a true "class I region" with tight linkage of genes encoding the class I presenting and processing molecules. Three paralogous regions of the human genome contain sets of linked genes homologous to various loci in the MHC class I, class II, and/or class III regions, providing insight into the organization of the "proto MHC" before the emergence of the adaptive immune system in the jawed vertebrates.

  10. Immune Adherence–mediated Opsonophagocytosis:  The Mechanism of Leishmania Infection

    PubMed Central

    Domínguez, Mercedes; Toraño, Alfredo

    1999-01-01

    To mimic the sandfly pool feeding process and characterize the cellular and biochemical events that occur during the early stages of promastigote–host interaction, we developed an ex vivo model of human blood infection with Leishmania promastigotes. Within 30 s of blood contact, Leishmania promastigotes bind natural anti–Leishmania antibodies, which then activate the classical complement pathway and opsonization by the third component of complement. The opsonized promastigotes undergo an immune adherence reaction and bind quantitatively to erythrocyte CR1 receptors; opsonized Leishmania amastigotes also bind to erythrocytes. Progression of infection implies promastigote transfer from erythrocytes to acceptor blood leukocytes. After 10 min of ex vivo infection, 25% of all leukocytes contain intracellular parasites, indicating that blood cells are the early targets for the invading promastigotes. We propose that adaptation to the immune adherence mechanism aids Leishmania survival, promoting rapid promastigote phagocytosis by leukocytes. This facilitates host colonization and may represent the parasite's earliest survival strategy. In light of this mechanism, it is unlikely that infection-blocking vaccines can be developed. PMID:9874561

  11. Adjuvant System AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity.

    PubMed

    Morel, Sandra; Didierlaurent, Arnaud; Bourguignon, Patricia; Delhaye, Sophie; Baras, Benoît; Jacob, Valérie; Planty, Camille; Elouahabi, Abdelatif; Harvengt, Pol; Carlsen, Harald; Kielland, Anders; Chomez, Patrick; Garçon, Nathalie; Van Mechelen, Marcelle

    2011-03-16

    AS03 is an Adjuvant System (AS) containing α-tocopherol and squalene in an oil-in-water (o/w) emulsion. AS03 has been considered for the development of pandemic and seasonal influenza vaccines. Key features of AS03's mode of action were investigated in vivo in mice and ex vivo in human cells. AS03's adjuvant activity was superior to that of aluminium hydroxide and required the spatio-temporal co-localisation of AS03 with the antigen. This requirement coincided with AS03 triggering a transient production of cytokines at the injection site and in the draining lymph nodes (dLNs). The nature of the cytokines produced was consistent with the enhanced recruitment of granulocytes and of antigen-loaded monocytes in the dLNs. The presence of α-tocopherol in AS03 was required for AS03 to achieve the highest antibody response. The presence of α-tocopherol also modulated the expression of some cytokines, including CCL2, CCL3, IL-6, CSF3 and CXCL1; increased the antigen loading in monocytes; and increased the recruitment of granulocytes in the dLNs. Hence, AS03's promotion of monocytes as the principal antigen-presenting cells, and its effects on granulocytes and cytokines, may all contribute to enhancing the antigen-specific adaptive immune response.

  12. Molecular mechanisms of HLA class I-mediated immune evasion of human tumors and their role in resistance to immunotherapies.

    PubMed

    Seliger, B

    2016-11-01

    Although the human immune system can recognize and eradicate tumor cells, tumors have also been shown to develop different strategies to escape immune surveillance, which has been described for the first time in different mouse models. The evasion of immune recognition was often associated with a poor prognosis and reduced survival of patients. During the last years the molecular mechanisms, which protect tumor cells from this immune attack, have been identified and appear to be more complex than initially expected. However, next to the composition of cellular, soluble and physical components of the tumor microenvironment, the tumor cells changes to limit immune responses. Of particular importance are classical and non-classical human leukocyte antigen (HLA) class I antigens, which often showed a deregulated expression in cancers of distinct origin. Furthermore, HLA class I abnormalities were linked to defects in the interferon signaling, which have both been shown to be essential for mounting immune responses and are involved in resistances to T cell-based immunotherapies. Therefore this review summarizes the expression, regulation, function and clinical relevance of HLA class I antigens in association with the interferon signal transduction pathway and its role in adaptive resistances to immunotherapies.

  13. 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.

  14. 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

  15. 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

  16. Manipulation of NKG2D Ligands by Cytomegaloviruses: Impact on Innate and Adaptive Immune Response

    PubMed Central

    Slavuljica, Irena; Krmpotić, Astrid; Jonjić, Stipan

    2011-01-01

    NKG2D is a potent activating receptor expressed on NK cells, NKT cells, γδ T cells, and CD8 T cells. NKG2D recognizes cell surface molecules structurally related to MHC class I proteins induced by infection or other type of cellular stress. The engagement of NKG2D leads to NK cell cytotoxicity and cytokine secretion or to a co-stimulation of CD8 T cells. Both human and mouse cytomegalovirus (CMV) have evolved numerous mechanisms to evade NKG2D-mediated immune response. This review describes the mechanisms used by CMV to inhibit NKG2D ligand expression and the recent advances in exploiting the NKG2D recognition pathway for mounting efficient and long-lasting immune response. PMID:22566874

  17. The influence of innate and adaptative immune responses on the differential clinical outcomes of leprosy.

    PubMed

    Fonseca, Adriana Barbosa de Lima; Simon, Marise do Vale; Cazzaniga, Rodrigo Anselmo; de Moura, Tatiana Rodrigues; de Almeida, Roque Pacheco; Duthie, Malcolm S; Reed, Steven G; de Jesus, Amelia Ribeiro

    2017-02-06

    Leprosy is a chronic infectious disease caused by Mycobacterium leprae. According to official reports from 121 countries across five WHO regions, there were 213 899 newly diagnosed cases in 2014. Although leprosy affects the skin and peripheral nerves, it can present across a spectrum of clinical and histopathological forms that are strongly influenced by the immune response of the infected individuals. These forms comprise the extremes of tuberculoid leprosy (TT), with a M. leprae-specific Th1, but also a Th17, response that limits M. leprae multiplication, through to lepromatous leprosy (LL), with M. leprae-specific Th2 and T regulatory responses that do not control M. leprae replication but rather allow bacterial dissemination. The interpolar borderline clinical forms present with similar, but less extreme, immune biases. Acute inflammatory episodes, known as leprosy reactions, are complications that may occur before, during or after treatment, and cause further neurological damages that can cause irreversible chronic disabilities. This review discusses the innate and adaptive immune responses, and their interactions, that are known to affect pathogenesis and influence the clinical outcome of leprosy.

  18. Habitat-specific adaptation of immune responses of stickleback (Gasterosteus aculeatus) lake and river ecotypes

    PubMed Central

    Scharsack, Jörn P; Kalbe, Martin; Harrod, Chris; Rauch, Gisep

    2007-01-01

    Freshwater populations of three-spined sticklebacks (Gasterosteus aculeatus) in northern Germany are found as distinct lake and river ecotypes. Adaptation to habitat-specific parasites might influence immune capabilities of stickleback ecotypes. Here, naive laboratory-bred sticklebacks from lake and river populations were exposed reciprocally to parasite environments in a lake and a river habitat. Sticklebacks exposed to lake conditions were infected with higher numbers of parasite species when compared with the river. River sticklebacks in the lake had higher parasite loads than lake sticklebacks in the same habitat. Respiratory burst, granulocyte counts and lymphocyte proliferation of head kidney leucocytes were increased in river sticklebacks exposed to lake when compared with river conditions. Although river sticklebacks exposed to lake conditions showed elevated activation of their immune system, parasites could not be diminished as effectively as by lake sticklebacks in their native habitat. River sticklebacks seem to have reduced their immune-competence potential due to lower parasite diversity in rivers. PMID:17426014

  19. Th17 cells confer long term adaptive immunity to oral mucosal Candida albicans infections

    PubMed Central

    Hernández-Santos, Nydiaris; Huppler, Anna R.; Peterson, Alanna C.; Khader, Shabaana A.; McKenna, Kyle C.; Gaffen, Sarah L.

    2012-01-01

    Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by Candida albicans. Despite its prevalence, little is known about C. albicans-specific immunity in the oral mucosa. Vaccines against Candida generate both Th1 and Th17 responses, and considerable evidence implicates IL-17 in immunity to OPC. However, IL-17 is also produced by innate immune cells that are remarkably similar to Th17 cells, expressing the same markers and localizing to similar mucosal sites. To date, the relative contribution(s) of Th1, Th17 and innate IL-17-producing cells in OPC have not been clearly defined. Here, we sought to determine the nature and function of adaptive T cell responses to OPC, using a new recall infection model. Mice subjected to infection and re-challenge with Candida mounted a robust and stable antigen specific IL-17 response in CD4+ but not CD8+ T cells. There was little evidence for Th1 or Th1/Th17 responses. The Th17 response promoted accelerated fungal clearance, and Th17 cells could confer protection in Rag1−/− mice upon adoptive transfer. Surprisingly, CD4 deficiency did not cause OPC, but was instead associated with compensatory IL-17 production by Tc17 and CD4-CD8-CD3+ cells. Therefore, classic CD4+Th17 cells protect from OPC, but can be compensated by other IL-17-producing cells in CD4-deficient hosts. PMID:23250275

  20. Impaired Adaptive Response to Mechanical Overloading in Dystrophic Skeletal Muscle

    PubMed Central

    Joanne, Pierre; Hourdé, Christophe; Ochala, Julien; Caudéran, Yvain; Medja, Fadia; Vignaud, Alban; Mouisel, Etienne; Hadj-Said, Wahiba; Arandel, Ludovic; Garcia, Luis; Goyenvalle, Aurélie; Mounier, Rémi; Zibroba, Daria; Sakamato, Kei; Butler-Browne, Gillian; Agbulut, Onnik; Ferry, Arnaud

    2012-01-01

    Dystrophin contributes to force transmission and has a protein-scaffolding role for a variety of signaling complexes in skeletal muscle. In the present study, we tested the hypothesis that the muscle adaptive response following mechanical overloading (ML) would be decreased in MDX dystrophic muscle lacking dystrophin. We found that the gains in muscle maximal force production and fatigue resistance in response to ML were both reduced in MDX mice as compared to healthy mice. MDX muscle also exhibited decreased cellular and molecular muscle remodeling (hypertrophy and promotion of slower/oxidative fiber type) in response to ML, and altered intracellular signalings involved in muscle growth and maintenance (mTOR, myostatin, follistatin, AMPKα1, REDD1, atrogin-1, Bnip3). Moreover, dystrophin rescue via exon skipping restored the adaptive response to ML. Therefore our results demonstrate that the adaptive response in response to ML is impaired in dystrophic MDX muscle, most likely because of the dystrophin crucial role. PMID:22511986

  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. Innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes.

    PubMed

    Pinschewer, Daniel D; Flatz, Lukas; Steinborn, Ralf; Horvath, Edit; Fernandez, Marylise; Lutz, Hans; Suter, Mark; Bergthaler, Andreas

    2010-09-01

    Arenaviruses such as Lassa virus (LASV) cause significant morbidity and mortality in endemic areas. Using a glycoprotein (GP) exchange strategy, we have recently developed live-attenuated arenavirus vaccine prototypes (rLCMV/VSVG) based on lymphocytic choriomeningitis virus (LCMV), a close relative of LASV. rLCMV/VSVG induced long-term CD8(+) T cell immunity against wild-type virus challenge and exhibited a stably attenuated phenotype in vivo. Here we elucidated the innate and adaptive immune requirements for the control of rLCMV/VSVG. Infection of RAG(-/-) mice resulted in persisting viral RNA in blood but not in overt viremia. The latter was only found in mice lacking both RAG and IFN type I receptor. Conversely, absence of IFN type II signaling or NK cells on an RAG-deficient background had only minor effects on vaccine virus load or none at all. rLCMV/VSVG infection of wild-type mice induced less type I IFN than did wild-type LCMV, and type I as well as type II IFNs were dispensable for the induction of virus-specific memory CD8 T cells and virus-neutralizing antibodies by rLCMV/VSVG. In conclusion, the adaptive immune systems are essential for elimination of rLCMV/VSVG, and type I but not type II IFN plays a major contributive role in lowering rLCMV/VSVG loads in vivo, attesting to the attenuation profile of the vaccine. Nevertheless, IFNs are not required for the induction of potent vaccine responses. These results provide a better understanding of the immunobiology of rLCMV/VSVG and will contribute to the further development of GP exchange vaccines for combating arenaviral hemorrhagic fevers.

  3. 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

  4. Interleukin-33 and Mast Cells Bridge Innate and Adaptive Immunity: From the Allergologist’s Perspective

    PubMed Central

    Jang, Tae Young; Kim, Young Hyo

    2015-01-01

    Interleukin (IL) 33, a member of the IL-1 superfamily, is an “alarmin” protein and is secreted in its active form from damaged cells undergoing necrotic cell death. Mast cells are one of the main effector cell types in allergic disorders. They secrete a variety of mediators, including T helper 2 cytokines. As mast cells have high-affinity IgE receptors (FcεRI) on their surface, they can capture circulating IgE. IgE-bound mast cells degranulate large amounts of histamine, heparin, and proteases when they encounter antigens. As IL-33 is an important mediator of innate immunity and mast cells play an important role in adaptive immune responses, interactions between the two could link innate and adaptive immunity. IL-33 promotes the adhesion of mast cells to laminin, fibronectin, and vitronectin. IL-33 increases the expression of adhesion molecules, such as intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, in endothelial cells, thus enhancing mast cell adhesion to blood vessel walls. IL-33 stimulates mast cell proliferation by activating the ST2/Myd88 pathway; increases mast cell survival by the activation of survival proteins such as Bcl-XL; and promotes the growth, development, and maturation of mast cell progenitors. IL-33 is also involved in the activation of mature mast cells and production of different proinflammatory cytokines. The interaction of IL-33 and mast cells could have important clinical implications in the field of clinical urology. Epithelial dysfunction and mast cells could play an important role in the pathogenesis of interstitial cystitis. Urinary levels of IL-33 significantly increase in patients with interstitial cystitis. In addition, the number of mast cells significantly increase in the urinary bladders of patients with interstitial cystitis. Therefore, inhibition of mast cell activation and degranulation in response to increase in IL-33 is a potential therapeutic target in the treatment of interstitial cystitis

  5. 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

  6. Effects of mechanical stimuli on adaptive remodeling of condylar cartilage.

    PubMed

    Sriram, D; Jones, A; Alatli-Burt, I; Darendeliler, M A

    2009-05-01

    Trabecular bone has been shown to be responsive to low-magnitude, high-frequency mechanical stimuli. This study aimed to assess the effects of these stimuli on condylar cartilage and its endochondral bone. Forty female 12-week-old C3H mice were divided into 3 groups: baseline control (killed at day 0), sham (killed at day 28 without exposure to mechanical stimuli), and experimental (killed following 28 days of exposure to mechanical stimuli). The experimental group was subjected to mechanical vibration of 30 Hz, for 20 minutes per day, 5 days per week, for 28 days. The specimens were analyzed by micro-computed tomography. The experimental group demonstrated a significant decrease in the volume of condylar cartilage and also a significant increase in bone histomorphometric parameters. The results suggest that the low-magnitude, high-frequency mechanical stimuli enhance adaptive remodeling of condylar cartilage, evidenced by the advent of endochondral bone replacing the hypertrophic cartilage.

  7. Adaptive mechanism-based congestion control for networked systems

    NASA Astrophysics Data System (ADS)

    Liu, Zhi; Zhang, Yun; Chen, C. L. Philip

    2013-03-01

    In order to assure the communication quality in network systems with heavy traffic and limited bandwidth, a new ATRED (adaptive thresholds random early detection) congestion control algorithm is proposed for the congestion avoidance and resource management of network systems. Different to the traditional AQM (active queue management) algorithms, the control parameters of ATRED are not configured statically, but dynamically adjusted by the adaptive mechanism. By integrating with the adaptive strategy, ATRED alleviates the tuning difficulty of RED (random early detection) and shows a better control on the queue management, and achieve a more robust performance than RED under varying network conditions. Furthermore, a dynamic transmission control protocol-AQM control system using ATRED controller is introduced for the systematic analysis. It is proved that the stability of the network system can be guaranteed when the adaptive mechanism is finely designed. Simulation studies show the proposed ATRED algorithm achieves a good performance in varying network environments, which is superior to the RED and Gentle-RED algorithm, and providing more reliable service under varying network conditions.

  8. Phenotypic Plasticity and Selection: Nonexclusive Mechanisms of Adaptation

    PubMed Central

    Grenier, S.; Barre, P.; Litrico, I.

    2016-01-01

    Selection and plasticity are two mechanisms that allow the adaptation of a population to a changing environment. Interaction between these nonexclusive mechanisms must be considered if we are to understand population survival. This review discusses the ways in which plasticity and selection can interact, based on a review of the literature on selection and phenotypic plasticity in the evolution of populations. The link between selection and phenotypic plasticity is analysed at the level of the individual. Plasticity can affect an individual's response to selection and so may modify the end result of genetic diversity evolution at population level. Genetic diversity increases the ability of populations or communities to adapt to new environmental conditions. Adaptive plasticity increases individual fitness. However this effect must be viewed from the perspective of the costs of plasticity, although these are not easy to estimate. It is becoming necessary to engage in new experimental research to demonstrate the combined effects of selection and plasticity for adaptation and their consequences on the evolution of genetic diversity. PMID:27313957

  9. Visual-adaptation-mechanism based underwater object extraction

    NASA Astrophysics Data System (ADS)

    Chen, Zhe; Wang, Huibin; Xu, Lizhong; Shen, Jie

    2014-03-01

    Due to the major obstacles originating from the strong light absorption and scattering in a dynamic underwater environment, underwater optical information acquisition and processing suffer from effects such as limited range, non-uniform lighting, low contrast, and diminished colors, causing it to become the bottleneck for marine scientific research and projects. After studying and generalizing the underwater biological visual mechanism, we explore its advantages in light adaption which helps animals to precisely sense the underwater scene and recognize their prey or enemies. Then, aiming to transform the significant advantage of the visual adaptation mechanism into underwater computer vision tasks, a novel knowledge-based information weighting fusion model is established for underwater object extraction. With this bionic model, the dynamical adaptability is given to the underwater object extraction task, making them more robust to the variability of the optical properties in different environments. The capability of the proposed method to adapt to the underwater optical environments is shown, and its outperformance for the object extraction is demonstrated by comparison experiments.

  10. Phenotypic Plasticity and Selection: Nonexclusive Mechanisms of Adaptation.

    PubMed

    Grenier, S; Barre, P; Litrico, I

    2016-01-01

    Selection and plasticity are two mechanisms that allow the adaptation of a population to a changing environment. Interaction between these nonexclusive mechanisms must be considered if we are to understand population survival. This review discusses the ways in which plasticity and selection can interact, based on a review of the literature on selection and phenotypic plasticity in the evolution of populations. The link between selection and phenotypic plasticity is analysed at the level of the individual. Plasticity can affect an individual's response to selection and so may modify the end result of genetic diversity evolution at population level. Genetic diversity increases the ability of populations or communities to adapt to new environmental conditions. Adaptive plasticity increases individual fitness. However this effect must be viewed from the perspective of the costs of plasticity, although these are not easy to estimate. It is becoming necessary to engage in new experimental research to demonstrate the combined effects of selection and plasticity for adaptation and their consequences on the evolution of genetic diversity.

  11. Centriole polarisation to the immunological synapse directs secretion from cytolytic cells of both the innate and adaptive immune systems

    PubMed Central

    2011-01-01

    Background Cytolytic cells of the immune system destroy pathogen-infected cells by polarised exocytosis of secretory lysosomes containing the pore-forming protein perforin. Precise delivery of this lethal hit is essential to ensuring that only the target cell is destroyed. In cytotoxic T lymphocytes (CTLs), this is accomplished by an unusual movement of the centrosome to contact the plasma membrane at the centre of the immunological synapse formed between killer and target cells. Secretory lysosomes are directed towards the centrosome along microtubules and delivered precisely to the point of target cell recognition within the immunological synapse, identified by the centrosome. We asked whether this mechanism of directing secretory lysosome release is unique to CTL or whether natural killer (NK) and invariant NKT (iNKT) cytolytic cells of the innate immune system use a similar mechanism to focus perforin-bearing lysosome release. Results NK cells were conjugated with B-cell targets lacking major histocompatibility complex class I 721.221 cells, and iNKT cells were conjugated with glycolipid-pulsed CD1-bearing targets, then prepared for thin-section electron microscopy. High-resolution electron micrographs of the immunological synapse formed between NK and iNKT cytolytic cells with their targets revealed that in both NK and iNKT cells, the centrioles could be found associated (or 'docked') with the plasma membrane within the immunological synapse. Secretory clefts were visible within the synapses formed by both NK and iNKT cells, and secretory lysosomes were polarised along microtubules leading towards the docked centrosome. The Golgi apparatus and recycling endosomes were also polarised towards the centrosome at the plasma membrane within the synapse. Conclusions These results reveal that, like CTLs of the adaptive immune system, the centrosomes of NK and iNKT cells (cytolytic cells of the innate immune system) direct secretory lysosomes to the immunological

  12. Immunizations

    MedlinePlus

    ... Get Weight Loss Surgery? A Week of Healthy Breakfasts Shyness Immunizations KidsHealth > For Teens > Immunizations Print A A A What's in this article? Why Are Vaccinations Important? Why Do I Need Shots? Which Vaccinations Do ...

  13. The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities.

    PubMed

    Huang, Zhi; Rose, Aaron H; Hoffmann, Peter R

    2012-04-01

    Dietary selenium (]Se), mainly through its incorporation into selenoproteins, plays an important role in inflammation and immunity. Adequate levels of Se are important for initiating immunity, but they are also involved in regulating excessive immune responses and chronic inflammation. Evidence has emerged regarding roles for individual selenoproteins in regulating inflammation and immunity, and this has provided important insight into mechanisms by which Se influences these processes. Se deficiency has long been recognized to negatively impact immune cells during activation, differentiation, and proliferation. This is related to increased oxidative stress, but additional functions such as protein folding and calcium flux may also be impaired in immune cells under Se deficient conditions. Supplementing diets with above-adequate levels of Se can also impinge on immune cell function, with some types of inflammation and immunity particularly affected and sexually dimorphic effects of Se levels in some cases. In this comprehensive article, the roles of Se and individual selenoproteins in regulating immune cell signaling and function are discussed. Particular emphasis is given to how Se and selenoproteins are linked to redox signaling, oxidative burst, calcium flux, and the subsequent effector functions of immune cells. Data obtained from cell culture and animal models are reviewed and compared with those involving human physiology and pathophysiology, including the effects of Se levels on inflammatory or immune-related diseases including anti-viral immunity, autoimmunity, sepsis, allergic asthma, and chronic inflammatory disorders. Finally, the benefits and potential adverse effects of intervention with Se supplementation for various inflammatory or immune disorders are discussed.

  14. Activation/modulation of adaptive immunity emerges simultaneously after 17DD yellow fever first-time vaccination: is this the key to prevent severe adverse reactions following immunization?

    PubMed Central

    Martins, M Â; Silva, M L; Marciano, A P V; Peruhype-Magalhães, V; Eloi-Santos, S M; Ribeiro, J G L; Correa-Oliveira, R; Homma, A; Kroon, E G; Teixeira-Carvalho, A; Martins-Filho, O A

    2007-01-01

    Over past decades the 17DD yellow fever vaccine has proved to be effective in controlling yellow fever and promises to be a vaccine vector for other diseases, but the cellular and molecular mechanisms by which it elicits such broad-based immunity are still unclear. In this study we describe a detailed phenotypic investigation of major and minor peripheral blood lymphocyte subpopulations aimed at characterizing the kinetics of the adaptive immune response following primary 17DD vaccination. Our major finding is a decreased frequency of circulating CD19+ cells at day 7 followed by emerging activation/modulation phenotypic features (CD19+interleukin(IL)10R+/CD19+CD32+) at day 15. Increased frequency of CD4+human leucocyte antigen D-related(HLA-DR+) at day 7 and CD8+HLA-DR+ at day 30 suggest distinct kinetics of T cell activation, with CD4+ T cells being activated early and CD8+ T cells representing a later event following 17DD vaccination. Up-regulation of modulatory features on CD4+ and CD8+ cells at day 15 seems to be the key event leading to lower frequency of CD38+ T cells at day 30. Taken together, our findings demonstrate the co-existence of phenotypic features associated with activation events and modulatory pathways. Positive correlations between CD4+HLA-DR+ cells and CD4+CD25high regulatory T cells and the association between the type 0 chemokine receptor CCR2 and the activation status of CD4+ and CD8+ cells further support this hypothesis. We hypothesize that this controlled microenviroment seems to be the key to prevent the development of serious adverse events, and even deaths, associated with the 17DD vaccine reported in the literature. PMID:17309541

  15. Adaptation.

    PubMed

    Broom, Donald M

    2006-01-01

    The term adaptation is used in biology in three different ways. It may refer to changes which occur at the cell and organ level, or at the individual level, or at the level of gene action and evolutionary processes. Adaptation by cells, especially nerve cells helps in: communication within the body, the distinguishing of stimuli, the avoidance of overload and the conservation of energy. The time course and complexity of these mechanisms varies. Adaptive characters of organisms, including adaptive behaviours, increase fitness so this adaptation is evolutionary. The major part of this paper concerns adaptation by individuals and its relationships to welfare. In complex animals, feed forward control is widely used. Individuals predict problems and adapt by acting before the environmental effect is substantial. Much of adaptation involves brain control and animals have a set of needs, located in the brain and acting largely via motivational mechanisms, to regulate life. Needs may be for resources but are also for actions and stimuli which are part of the mechanism which has evolved to obtain the resources. Hence pigs do not just need food but need to be able to carry out actions like rooting in earth or manipulating materials which are part of foraging behaviour. The welfare of an individual is its state as regards its attempts to cope with its environment. This state includes various adaptive mechanisms including feelings and those which cope with disease. The part of welfare which is concerned with coping with pathology is health. Disease, which implies some significant effect of pathology, always results in poor welfare. Welfare varies over a range from very good, when adaptation is effective and there are feelings of pleasure or contentment, to very poor. A key point concerning the concept of individual adaptation in relation to welfare is that welfare may be good or poor while adaptation is occurring. Some adaptation is very easy and energetically cheap and

  16. Adaptive mechanical-wetting lens actuated by ferrofluids

    NASA Astrophysics Data System (ADS)

    Cheng, Hui-Chuan; Xu, Su; Liu, Yifan; Levi, Shoshana; Wu, Shin-Tson

    2011-04-01

    We report an adaptive mechanical-wetting lens actuated by ferrofluids. The ferrofluids works like a piston to pump liquids in and out from the lens chamber, which in turn reshapes the lens curvature and changes the focal length. Both positive and negative lenses are demonstrated experimentally. The ferrofluid-actuated mechanical-wetting lens exhibits some attractive features, such as high resolution, fast response time, low power consumption, simple structure and electronic control, weak gravity effect, and low cost. Its potential applications in medical imaging, surveillance, and commercial electronics are foreseeable.

  17. The Role of Plasmacytoid Dendritic Cells in Innate and Adaptive Immune Responses against Alpha Herpes Virus Infections

    PubMed Central

    Schuster, Philipp; Boscheinen, Jan Bernardin; Tennert, Karin; Schmidt, Barbara

    2011-01-01

    In 1999, two independent groups identified plasmacytoid dendritic cells (PDC) as major type I interferon- (IFN-) producing cells in the blood. Since then, evidence is accumulating that PDC are a multifunctional cell population effectively coordinating innate and adaptive immune responses. This paper focuses on the role of different immune cells and their interactions in the surveillance of alpha herpes virus infections, summarizes current knowledge on PDC surface receptors and their role in direct cell-cell contacts, and develops a risk factor model for the clinical implications of herpes simplex and varicella zoster virus reactivation. Data from studies involving knockout mice and cell-depletion experiments as well as human studies converge into a “spider web”, in which the direct and indirect crosstalk between many cell populations tightly controls acute, latent, and recurrent alpha herpes virus infections. Notably, cells involved in innate immune regulations appear to shape adaptive immune responses more extensively than previously thought. PMID:22312349

  18. Programmed death ligand 1 as an indicator of pre-existing adaptive immune responses in human hepatocellular carcinoma.

    PubMed

    Xie, Qian-Kun; Zhao, Yu-Jie; Pan, Tao; Lyu, Ning; Mu, Lu-Wen; Li, Shao-Long; Shi, Mu-De; Zhang, Zhen-Feng; Zhou, Peng-Hui; Zhao, Ming

    2016-07-01

    It is well known that the aberrant expression of programmed death ligand 1 (PD-L1) on tumor cells impairs antitumor immunity. To date, in hepatocellular carcinoma (HCC), the relationship between PD-L1 expression and host-tumor immunity is not well defined. Here, the expression levels of PD-L1 and CD8(+) T cell infiltration were analyzed by immunohistochemistry (IHC) in formalin fixed paraffin embedded (FFPE) specimens from 167 HCC patients undergoing resection. A significant positive association was found between PD-L1 expression and the presence of CD8(+) T cell (p < 0.0001). Moreover, constitutive PD-L1 protein expression was not detected by western blot in HepG2, Hep3B, and 7402 HCC cancer cell lines; but co-cultured these cell lines with INFγ, a cytokine produced by activated CD8(+) T cells, remarkably upregulated PD-L1 expression. In fresh frozen HCC specimens, INFγ was found to be significantly correlated with PD-L1 and CD8(+) gene expression, as evaluated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). These findings indicate that increased PD-L1 level may represent an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous antitumor activity. Both increased intratumoral PD-L1 and CD8(+) were significantly associated with superior DFS (CD8(+): p = 0.03; PD-L1: p = 0.023) and OS (CD8(+): p = 0.001 and PD-L1: p = 0.059), but PD-L1 expression was not independently prognostic. In conclusions, PD-L1 upregulation is mainly induced by activated CD8(+) cytotoxic T cells pre-existing in HCC milieu rather than be constitutively expressed by the tumor cells, and it is a favorable prognostic factor for HCC.

  19. In vivo deployment of mechanically adaptive nanocomposites for intracortical microelectrodes

    PubMed Central

    Harris, J P; Hess, A E; Rowan, S J; Weder, C; Zorman, C A; Tyler, D J; Capadona, J R

    2012-01-01

    We recently introduced a series of stimuli-responsive, mechanically-adaptive polymer nanocomposites. Here, we report the first application of these bio-inspired materials as substrates for intracortical microelectrodes. Our hypothesis is that the ideal electrode should be initially stiff to facilitate minimal trauma during insertion into the cortex, yet becomes mechanically compliant to match the stiffness of the brain tissue and minimize forces exerted on the tissue, attenuating inflammation. Microprobes created from mechanically reinforced nanocomposites demonstrated a significant advantage compared to model microprobes composed of neat polymer only. The nanocomposite microprobes exhibit a higher storage modulus (E’ = ~5 GPa) than the neat polymer microprobes (E’ = ~2 GPa) and could sustain higher loads (~17 mN), facilitating penetration through the pia mater and insertion into the cerebral cortex of a rat. In contrast, the neat polymer microprobes mechanically failed under lower loads (~7 mN) before they were capable of inserting into cortical tissue. Further, we demonstrated the material’s ability to morph while in the rat cortex to more closely match the mechanical properties of the cortical tissue. Nanocomposite microprobes that were implanted into the rat cortex for up to 8 weeks demonstrated increased cell density at the microelectrode-tissue interface and a lack of tissue necrosis or excessive gliosis. This body of work introduces our nanocomposite-based microprobes as adaptive substrates for intracortical microelectrodes and potentially other biomedical applications. PMID:21654037

  20. Immune mechanisms of allergen-specific sublingual immunotherapy.

    PubMed

    Moingeon, P; Batard, T; Fadel, R; Frati, F; Sieber, J; Van Overtvelt, L

    2006-02-01

    Sublingual immunotherapy has been shown in some clinical studies to modulate allergen-specific antibody responses [with a decrease in the immunoglobulin E/immunoglobulin G4 (IgE/IgG4) ratio] and to reduce the recruitment and activation of proinflammatory cells in target mucosa. Whereas a central paradigm for successful immunotherapy has been to reorient the pattern of allergen-specific T-cell responses in atopic patients from a T helper (Th)2 to Th1 profile, there is currently a growing interest in eliciting regulatory T cells, capable of downregulating both Th1 and Th2 responses through the production of interleukin (IL)-10 and/or transforming growth factor (TGF)-beta. We discuss herein immune mechanisms involved during allergen-specific sublingual immunotherapy (SLIT), in comparison with subcutaneous immunotherapy. During SLIT, the allergen is captured within the oral mucosa by Langerhans-like dendritic cells expressing high-affinity IgE receptors, producing IL-10 and TGF-beta, and upregulating indoleamine dioxygenase (IDO), suggesting that such cells are prone to induce tolerance. The oral mucosa contains limited number of proinflammatory cells, such as mast cells, thereby explaining the well-established safety profile of SLIT. In this context, second-generation vaccines based on recombinant allergens in a native conformation formulated with adjuvants are designed to target Langerhans-like cells in the sublingual mucosa, with the aim to induce allergen-specific regulatory T cells. Importantly, such recombinant vaccines should facilitate the identification of biological markers of SLIT efficacy in humans.

  1. In defense of phage: viral suppressors of CRISPR-mediated adaptive immunity in bacteria.

    PubMed

    Wiedenheft, Blake

    2013-05-01

    Viruses that infect bacteria are the most abundant biological agents on the planet and bacteria have evolved diverse defense mechanisms to combat these genetic parasites. One of these bacterial defense systems relies on a repetitive locus, referred to as a CRISPR (clusters of regularly interspaced short palindromic repeats). Bacteria and archaea acquire resistance to invading viruses and plasmids by integrating short fragments of foreign nucleic acids at one end of the CRISPR locus. CRISPR loci are transcribed and the long primary CRISPR transcript is processed into a library of small RNAs that guide the immune system to invading nucleic acids, which are subsequently degraded by dedicated nucleases. However, the development of CRISPR-mediated immune systems has not eradicated phages, suggesting that viruses have evolved mechanisms to subvert CRISPR-mediated protection. Recently, Bondy-Denomy and colleagues discovered several phage-encoded anti-CRISPR proteins that offer new insight into the ongoing molecular arms race between viral parasites and the immune systems of their hosts.

  2. Mechanisms of colour adaptation in the prawn Penaeus monodon.

    PubMed

    Wade, Nicholas M; Anderson, Mike; Sellars, Melony J; Tume, Ron K; Preston, Nigel P; Glencross, Brett D

    2012-01-15

    Exposure of prawns to dark- or light-coloured substrates is known to trigger a strong colour adaptation response through expansion or contraction of the colouration structures in the prawn hypodermis. Despite the difference in colour triggered by this adaptive response, total levels of the predominant carotenoid pigment, astaxanthin, are not modified, suggesting that another mechanism is regulating this phenomenon. Astaxanthin binds to a specific protein called crustacyanin (CRCN), and it is the interaction between the quantities of each of these compounds that produces the diverse range of colours seen in crustacean shells. In this study, we investigated the protein changes and genetic regulatory processes that occur in prawn hypodermal tissues during adaptation to black or white substrates. The amount of free astaxanthin was higher in animals adapted to dark substrate compared with those adapted to light substrate, and this difference was matched by a strong elevation of CRCN protein. However, there was no difference in the expression of CRCN genes either across the moult cycle or in response to background substrate colour. These results indicate that exposure to a dark-coloured substrate causes an accumulation of CRCN protein, bound with free astaxanthin, in the prawn hypodermis without modification of CRCN gene expression. On light-coloured substrates, levels of CRCN protein in the hypodermis are reduced, but the carotenoid is retained, undispersed in the hypodermal tissue, in an esterified form. Therefore, the abundance of CRCN protein affects the distribution of pigment in prawn hypodermal tissues, and is a crucial regulator of the colour adaptation response in prawns.

  3. Restricted autoantigen recognition associated with deletional and adaptive regulatory mechanisms.

    PubMed

    Gebe, John A; Yue, Betty B; Unrath, Kelly A; Falk, Ben A; Nepom, Gerald T

    2009-07-01

    Autoimmune diabetes (T1D) is characterized by CD4(+) T cell reactivity to a variety of islet-associated Ags. At-risk individuals, genetically predisposed to T1D, often have similar T cell reactivity, but nevertheless fail to progress to clinically overt disease. To study the immune tolerance and regulatory environment permissive for such autoreactive T cells, we expressed TCR transgenes derived from two autoreactive human T cells, 4.13 and 164, in HLA-DR4 transgenic mice on a C57BL/6-derived "diabetes-resistant" background. Both TCR are responsive to an immunodominant epitope of glutamic acid decarboxylase 65(555-567), which is identical in sequence between humans and mice, is restricted by HLA-DR4, and is a naturally processed self Ag associated with T1D. Although both TCR use the identical Valpha and Vbeta genes, differing only in CDR3, we found stark differences in the mechanisms utilized in vivo in the maintenance of immune tolerance. A combination of thymic deletion (negative selection), TCR down-regulation, and peripheral activation-induced cell death dominated the phenotype of 164 T cells, which nevertheless still maintain their Ag responsiveness in the periphery. In contrast, 4.13 T cells are much less influenced by central and deletional tolerance mechanisms, and instead display a peripheral immune deviation including differentiation into IL-10-secreting Tr1 cells. These findings indicate a distinct set of regulatory alternatives for autoreactive T cells, even within a single highly restricted HLA-peptide-TCR recognition profile.

  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

    Human infections with avian influenza A viruses (IAVs) without or with clinical symptoms of disease were recently reported from several continents, mainly in high risk groups of people, who came into the contact with infected domestic birds or poultry. It was shown that avian IAVs are able to infect humans directly without previous adaptation, however, their ability to replicate and to cause a disease in this new host can differ. No spread of these avian IAVs among humans has been documented until now, except for one case described in Netherlands in the February of 2003 in people directly involved in handling IAV (H7N7)-infected poultry. The aim of our work was to examine whether a low pathogenic avian IAV can induce a virus-specific immune response of biological relevancy, in spite of its restricted replication in mammals. As a model we used a low pathogenic virus A/Duck/Czechoslovakia/1956 (H4N6) (A/Duck), which replicated well in MDCK cells and produced plaques on cell monolayers, but was unable to replicate productively in mouse lungs. We examined how the immune system of mice responds to the intranasal application of this non-adapted avian virus. Though we did not prove the infectious virus in lungs of mice following A/Duck application even after its multiple passaging in mice, we detected virus-specific vRNA till day 8 post infection. Moreover, we detected virus-specific mRNA and de novo synthesized viral nucleoprotein (NP) and membrane protein (M1) in lungs of mice on day 2 and 4 after exposure to A/Duck. Virus-specific antibodies in sera of these mice were detectable by ELISA already after a single intranasal dose of A/Duck virus. Not only antibodies specific to the surface glycoprotein hemagglutinin (HA) were induced, but also antibodies specific to the NP and M1 of IAV were detected by Western blot and their titers increased after the second exposure of mice to this virus. Importantly, antibodies neutralizing virus A/Duck were proved in mouse

  5. Recent progress in the understanding of host immunity to avian coccidiosis: IL-17 family cytokines as the sentinels on the intestinal mucosa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The molecular and cellular mechanisms leading to immune protection against Eimeria avian coccidiosis are complex and include multiple aspects of innate and adaptive immunities. Innate immunity is mediated by various subpopulations of immune cells that recognize pathogen associated molecular patterns...

  6. Novel pathogenetic mechanisms and structural adaptations in ischemic mitral regurgitation.

    PubMed

    Silbiger, Jeffrey J

    2013-10-01

    Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction thought to result from leaflet tethering caused by displacement of the papillary muscles that occurs as the left ventricle remodels. The author explores the possibility that left atrial remodeling may also play a role in the pathogenesis of ischemic MR, through a novel mechanism: atriogenic leaflet tethering. When ischemic MR is hemodynamically significant, the left ventricle compensates by dilating to preserve forward output using the Starling mechanism. Left ventricular dilatation, however, worsens MR by increasing the mitral valve regurgitant orifice, leading to a vicious cycle in which MR begets more MR. The author proposes that several structural adaptations play a role in reducing ischemic MR. In contrast to the compensatory effects of left ventricular enlargement, these may reduce, rather than increase, its severity. The suggested adaptations involve the mitral valve leaflets, the papillary muscles, the mitral annulus, and the left ventricular false tendons. This review describes the potential role each may play in reducing ischemic MR. Therapies that exploit these adaptations are also discussed.

  7. Explicit mentalizing mechanisms and their adaptive role in memory conformity.

    PubMed

    Wheeler, Rebecca; Allan, Kevin; Tsivilis, Dimitris; Martin, Douglas; Gabbert, Fiona

    2013-01-01

    Memory conformity occurs when an individual endorses what other individuals remember about past events. Research on memory conformity is currently dominated by a 'forensic' perspective, which views the phenomenon as inherently undesirable. This is because conformity not only distorts the accuracy of an individual's memory, but also produces false corroboration between individuals, effects that act to undermine criminal justice systems. There is growing awareness, however, that memory conformity may be interpreted more generally as an adaptive social behavior regulated by explicit mentalizing mechanisms. Here, we provide novel evidence in support of this emerging alternative theoretical perspective. We carried out a memory conformity experiment which revealed that explicit belief-simulation (i.e. using one's own beliefs to model what other people believe) systematically biases conformity towards like-minded individuals, even when there is no objective evidence that they have a more accurate memory than dissimilar individuals. We suggest that this bias is functional, i.e. adaptive, to the extent that it fosters trust, and hence cooperation, between in-group versus out-group individuals. We conclude that memory conformity is, in more fundamental terms, a highly desirable product of explicit mentalizing mechanisms that promote adaptive forms of social learning and cooperation.

  8. Unique Roles of TLR9- and MyD88-Dependent and -Independent Pathways in Adaptive Immune Responses to AAV-Mediated Gene Transfer.

    PubMed

    Rogers, Geoffrey L; Suzuki, Masataka; Zolotukhin, Irene; Markusic, David M; Morel, Laurence M; Lee, Brendan; Ertl, Hildegund C J; Herzog, Roland W

    2015-01-01

    The immune system represents a significant barrier to successful gene therapy with adeno-associated viral (AAV) vectors. In particular, adaptive immune responses to the viral capsid or the transgene product are of concern. The sensing of AAV by toll-like receptors (TLRs) TLR2 and TLR9 has been suggested to play a role in innate immunity to the virus and may also shape subsequent adaptive immune responses. Here, we investigated the functions of TLR2, TLR9 and the downstream signaling adaptor MyD88 in antibody and CD8+ T-cell responses. Antibody formation against the transgene product occurred largely independently of TLR signaling following gene transfer with AAV1 or AAV2 vectors, whereas loss of signaling through the TLR9-MyD88 pathway substantially reduced CD8+ T-cell responses. In contrast, MyD88 (but neither of the TLRs) regulated antibody responses to capsid. B cell-intrinsic MyD88 was required for the formation of anti-capsid IgG2c independently of vector serotype or route of administration. However, MyD88(-/-) mice instead produced anti-capsid IgG1 that emerged with delayed kinetics but nonetheless completely prevented in vivo readministration. We conclude that there are distinct roles for TLR9 and MyD88 in promoting adaptive immune responses to AAV-mediated gene transfer and that there are redundant MyD88-dependent and MyD88-independent mechanisms that stimulate neutralizing antibody formation against AAV.

  9. Senescent Remodeling of the Innate and Adaptive Immune System in the Elderly Men with Prostate Cancer

    PubMed Central

    Taverna, Gianluigi; Seveso, Mauro; Giusti, Guido; Hurle, Rodolfo; Graziotti, Pierpaolo; Štifter, Sanja; Chiriva-Internati, Maurizio; Grizzi, Fabio

    2014-01-01

    Despite years of intensive investigation that has been made in understanding prostate cancer, it remains a major cause of death in men worldwide. Prostate cancer emerges from multiple alterations that induce changes in expression patterns of genes and proteins that function in networks controlling critical cellular events. Based on the exponential aging of the population and the increasing life expectancy in industrialized Western countries, prostate cancer in the elderly men is becoming a disease of increasing significance. Aging is a progressive degenerative process strictly integrated with inflammation. Several theories have been proposed that attempt to define the role of chronic inflammation in aging including redox stress, mitochondrial damage, immunosenescence, and epigenetic modifications. Here, we review the innate and adaptive immune systems and their senescent remodeling in elderly men with prostate cancer. PMID:24772169

  10. CRISPR-Cas: From the Bacterial Adaptive Immune System to a Versatile Tool for Genome Engineering.

    PubMed

    Kirchner, Marion; Schneider, Sabine

    2015-11-09

    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.

  11. Adaptation Mechanisms in the Evolution of Moss Defenses to Microbes

    PubMed Central

    Ponce de León, Inés; Montesano, Marcos

    2017-01-01

    Bryophytes, including mosses, liverworts and hornworts are early land plants that have evolved key adaptation mechanisms to cope with abiotic stresses and microorganisms. Microbial symbioses facilitated plant colonization of land by enhancing nutrient uptake leading to improved plant growth and fitness. In addition, early land plants acquired novel defense mechanisms to protect plant tissues from pre-existing microbial pathogens. Due to its evolutionary stage linking unicellular green algae to vascular plants, the non-vascular moss Physcomitrella patens is an interesting organism to explore the adaptation mechanisms developed in the evolution of plant defenses to microbes. Cellular and biochemical approaches, gene expression profiles, and functional analysis of genes by targeted gene disruption have revealed that several defense mechanisms against microbial pathogens are conserved between mosses and flowering plants. P. patens perceives pathogen associated molecular patterns by plasma membrane receptor(s) and transduces the signal through a MAP kinase (MAPK) cascade leading to the activation of cell wall associated defenses and expression of genes that encode proteins with different roles in plant resistance. After pathogen assault, P. patens also activates the production of ROS, induces a HR-like reaction and increases levels of some hormones. Furthermore, alternative metabolic pathways are present in P. patens leading to the production of a distinct metabolic scenario than flowering plants that could contribute to defense. P. patens has acquired genes by horizontal transfer from prokaryotes and fungi, and some of them could represent adaptive benefits for resistance to biotic stress. In this review, the current knowledge related to the evolution of plant defense responses against pathogens will be discussed, focusing on the latest advances made in the model plant P. patens. PMID:28360923

  12. Adaptation Mechanisms in the Evolution of Moss Defenses to Microbes.

    PubMed

    Ponce de León, Inés; Montesano, Marcos

    2017-01-01

    Bryophytes, including mosses, liverworts and hornworts are early land plants that have evolved key adaptation mechanisms to cope with abiotic stresses and microorganisms. Microbial symbioses facilitated plant colonization of land by enhancing nutrient uptake leading to improved plant growth and fitness. In addition, early land plants acquired novel defense mechanisms to protect plant tissues from pre-existing microbial pathogens. Due to its evolutionary stage linking unicellular green algae to vascular plants, the non-vascular moss Physcomitrella patens is an interesting organism to explore the adaptation mechanisms developed in the evolution of plant defenses to microbes. Cellular and biochemical approaches, gene expression profiles, and functional analysis of genes by targeted gene disruption have revealed that several defense mechanisms against microbial pathogens are conserved between mosses and flowering plants. P. patens perceives pathogen associated molecular patterns by plasma membrane receptor(s) and transduces the signal through a MAP kinase (MAPK) cascade leading to the activation of cell wall associated defenses and expression of genes that encode proteins with different roles in plant resistance. After pathogen assault, P. patens also activates the production of ROS, induces a HR-like reaction and increases levels of some hormones. Furthermore, alternative metabolic pathways are present in P. patens leading to the production of a distinct metabolic scenario than flowering plants that could contribute to defense. P. patens has acquired genes by horizontal transfer from prokaryotes and fungi, and some of them could represent adaptive benefits for resistance to biotic stress. In this review, the current knowledge related to the evolution of plant defense responses against pathogens will be discussed, focusing on the latest advances made in the model plant P. patens.

  13. Bioindicators of immune function in creosote-adapted estuarine killifish, Fundulus heteroclitus.

    PubMed

    Frederick, Lee A; Van Veld, Peter A; Rice, Charles D

    2007-09-01

    Several populations of the estuarine killifish, Fundulus heteroclitus, also known as the mummichog, exhibit characteristics of adaptation to priority pollutants. One such population of mummichog inhabits the Elizabeth River in Virginia at the Atlantic Wood site (AW), a U.S. Environmental Protection Agency (EPA) Superfund site heavily contaminated with creosote containing a mixture of polyaromatic hydrocarbons (PAHs). Although PAHs are known to be immunotoxic in experimental animals, resident AW mummichogs seem to thrive. Mummichogs from the AW site and a reference site were subsequently examined over a 2-yr period for total immunoglobin (IgM), as well as circulating antibody levels against 5 ubiquitous marine bacteria. Expression profiles of circulating and lymphoid lysozyme and lymphoid cyclooxygenase-2 (COX-2) were also examined. Compared to relatively high total IgM and specific antibody responses in reference fish, AW mummichogs had lower circulating IgM and lower specific antibody levels against all bacteria examined, however they had higher levels of circulating lysozyme. Lymphoid cells in the AW mummichogs also expressed higher levels of lysozyme, as well as COX-2, which may indicate a state of macrophage activation. Elevated COX-2 levels may be associated with enhanced metabolism of PAHs through cooxidation-peroxidase pathways. Additional studies attempted to immunize AW mummichogs reared in uncontaminated water to compare their antibody responses to that of reference fish. AW mummichogs did not survive 40 d post culture, while reference fish thrived. Our findings suggest that the chemical environment at the AW site may be vicariously enhancing components of innate immunity, probably through oxidative stress pathways, in resident mummichogs, while actively suppressing humoral immune responses.

  14. Innate-Adaptive Crosstalk: How Dendritic Cells Shape Immune Responses in the CNS

    PubMed Central

    Héninger, Erika; Harris, Melissa G; Lee, JangEun; Sandor, Matyas; Fabry, Zsuzsanna

    2013-01-01

    Dendritic cells (DCs) are a heterogeneous group of professional antigen presenting cells that lie in a nexus between innate and adaptive immunity because they recognize and respond to danger signals and subsequently initiate and regulate effector T-cell responses. Initially thought to be absent from the CNS, both plasmacytoid and conventional DCs as well as DC precursors have recently been detected in several CNS compartments where they are seemingly poised for responding to injury and pathogens. Additionally, monocyte-derived DCs rapidly accumulate in the inflamed CNS where they, along with other DC subsets, may function to locally regulate effector T-cells and/or carry antigens to CNS-draining cervical lymph nodes. In this review we highlight recent research showing that (a) distinct inflammatory stimuli differentially recruit DC subsets to the CNS; (b) DC recruitment across the blood-brain barrier (BBB) is regulated by adhesion molecules, growth factors, and chemokines; and (c) DCs positively or negatively regulate immune responses in the CNS. PMID:21948376

  15. 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.

  16. 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.

  17. Immune Mechanisms in Medium and Large Vessel Vasculitis

    PubMed Central

    Weyand, Cornelia M.; Goronzy, Jörg J.

    2014-01-01

    Summary Vasculitis of the medium and large arteries, most often presenting as giant cell arteritis (GCA), is an infrequent, but potentially fatal type of immune-mediated vascular disease. The site of the aberrant immune reaction, the mural layers of the artery, is strictly defined by vascular dendritic cells, endothelial cells, vascular smooth muscle cells and fibroblasts which engage in an interaction with T cells and macrophages to ultimately cause luminal stenosis or aneurysmal wall damage of the vessel. A multitude of effector cytokines, all known as critical mediators in host-protective immunity, has been identified in the vasculitic lesions. Two dominant cytokine clusters, one centering on the IL-6/IL-17 axis, the other on the IL-12/IFN-γ axis, have been connected with disease activity. These two clusters appear to serve different roles in the vasculitic process. The IL-6/IL-17 cluster is highly responsive to standard corticosteroid therapy, whereas the IL-12/IFN-γ cluster is resistant to steroid-mediated immunosuppression. The information exchange between vascular and immune cells and stabilization of the vasculitic process involves members of the NOTCH receptor and ligand family. Focusing on elements in the tissue context of GCA, instead of broadly suppressing host immunity, may allow for a more tailored therapeutic approach and spare patients the unwanted side-effects of aggressive immunosuppression. PMID:24189842

  18. Mechanism of Thermal Adaptation in the Lactate Dehydrogenases.

    PubMed

    Peng, Huo-Lei; Egawa, Tsuyoshi; Chang, Eric; Deng, Hua; Callender, Robert

    2015-12-10

    The mechanism of thermal adaptation of enzyme function at the molecular level is poorly understood but is thought to lie within the structure of the protein or its dynamics. Our previous work on pig heart lactate dehydrogenase (phLDH) has determined very high resolution structures of the active site, via isotope edited IR studies, and has characterized its dynamical nature, via laser-induced temperature jump (T-jump) relaxation spectroscopy on the Michaelis complex. These particular probes are quite powerful at getting at the interplay between structure and dynamics in adaptation. Hence, we extend these studies to the psychrophilic protein cgLDH (Champsocephalus gunnari; 0 °C) and the extreme thermophile tmLDH (Thermotoga maritima LDH; 80 °C) for comparison to the mesophile phLDH (38-39 °C). Instead of the native substrate pyruvate, we utilize oxamate as a nonreactive substrate mimic for experimental reasons. Using isotope edited IR spectroscopy, we find small differences in the substate composition that arise from the detailed bonding patterns of oxamate within the active site of the three proteins; however, we find these differences insufficient to explain the mechanism of thermal adaptation. On the other hand, T-jump studies of reduced β-nicotinamide adenine dinucleotide (NADH) emission reveal that the most important parameter affecting thermal adaptation appears to be enzyme control of the specific kinetics and dynamics of protein motions that lie along the catalytic pathway. The relaxation rate of the motions scale as cgLDH > phLDH > tmLDH in a way that faithfully matches kcat of the three isozymes.

  19. Insight into the mechanisms regulating immune homeostasis in health and disease.

    PubMed

    Sirisinha, Stitaya

    2011-03-01

    Innate and adaptive immune systems consist of cells and molecules that work together in concert to fight against microbial infection and maintain homeostasis. Hosts encounter microbes / exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) all the time and they must have proper mechanisms to counteract the danger such that appropriate responses (e.g., degree of inflammation and types of mediators induced) can be mounted in different scenarios. Increasing numbers of endogenous danger signals of host origin are being identified including, for example, uric acid and cholesterol crystals, high mobility group box1 (HMGB1) protein, oxidized LDL, vesicans, heat shock proteins (HSPs) and self DNA. Many of these endogenous ligands have been shown to be associated with inflammation-related diseases like atherosclerosis, gout and type 2 diabetes. Several DAMPs appear to have the ability to interact with more than one receptor. We are now beginning to understand how the immune system can distinguish infection from endogenous ligands elaborated following cellular insults and tissue damage. Appropriate responses to maintain the homeostatic state in health and disease depend largely on the recognition and response to these stimuli by germline encoded pattern-recognition receptors (PRRs) present on both immune and non-immune cells. These receptors are, for example, Toll-like receptors (TLRs), C-type lectin receptors (CLRs) and cytosolic receptors (e.g., RLRs, NLRs and some intracellular DNA sensors). Atypical PRR "danger" receptors, like the receptor for advanced glycation end products (RAGE) and their ligands have been identified. A proper response to maintain homeostasis relies on specific negative regulators and regulatory pathways to dampen its response to tissue injury while maintaining the capacity to eliminate infection and induce proper tissue repair. Moreover, some PRRs (e.g., TLR2,TLR4 and NLRP3) and atypical

  20. Influence of Immunotherapy with Autologous Dendritic Cells on Innate and Adaptive Immune Response in Cancer

    PubMed Central

    Matias, Bruna F.; de Oliveira, Tânia M.; Rodrigues, Cláudia M.; Abdalla, Douglas R.; Montes, Letícia; Murta, Eddie F.C.; Michelin, Márcia A.

    2013-01-01

    The objective of this study was to evaluate some of the mechanisms involved in the activation of the immune system in patients with advanced-stage cancer (n = 7) who received an autologous dendritic cell vaccine. We examined the immune response mediated by macrophages (CD14+), natural killer cells (CD56+), and B lymphocytes (CD19+) by flow cytometry and assessed the expression of Th1 (IFN-γ, TNF-α, IL-2, and IL-12), Th2 (IL-4), and Treg (TGF-β) cytokines by flow cytometry and an enzyme-linked immunosorbent assay. The CD14+ TNF-α+ population was significantly increased (P < 0.04) when patients received the vaccine; IL-2 expression in both NK cells and in B lymphocytes was increased after a transient initial increase showed a nearly significant decrease (P < 0.07 and P < 0.06 respectively), whereas the CD19+ and CD56+ populations did not show significant changes. Dendritic cell-based immunotherapy led to increased secretion of IFN-γ and IL-12 and reduced secretion of TGF-β. In conclusion, it is likely that the autologous dendritic cell vaccine stimulated the immune cells from the peripheral blood of patients with cancer and generally increased the production of Th1 cytokines, which are related to immunomodulatory responses against cancer. PMID:23926442

  1. Cas1-Cas2 complex formation mediates spacer acquisition during CRISPR-Cas adaptive immunity.

    PubMed

    Nuñez, James K; Kranzusch, Philip J; Noeske, Jonas; Wright, Addison V; Davies, Christopher W; Doudna, Jennifer A

    2014-06-01

    The initial stage of CRISPR-Cas immunity involves the integration of foreign DNA spacer segments into the host genomic CRISPR locus. The nucleases Cas1 and Cas2 are the only proteins conserved among all CRISPR-Cas systems, yet the molecular functions of these proteins during immunity are unknown. Here we show that Cas1 and Cas2 from Escherichia coli form a stable complex that is essential for spacer acquisition and determine the 2.3-Å-resolution crystal structure of the Cas1-Cas2 complex. Mutations that perturb Cas1-Cas2 complex formation disrupt CRISPR DNA recognition and spacer acquisition in vivo. Active site mutants of Cas2, unlike those of Cas1, can still acquire new spacers, thus indicating a nonenzymatic role of Cas2 during immunity. These results reveal the universal roles of Cas1 and Cas2 and suggest a mechanism by which Cas1-Cas2 complexes specify sites of CRISPR spacer integration.

  2. Application of flexure structures to active and adaptive opto-mechanical mechanisms

    NASA Astrophysics Data System (ADS)

    Zago, Lorenzo; Genequand, Pierre M.; Kjelberg, Ivar; Morschel, Joseph

    1997-03-01

    Active and adaptive structures, also commonly called 'smart' structures, combine in one integrated system various functions such as load carrying and structural function, mechanical (cinematic) functions, sensing, control and actuating. Originally developed for high accuracy opto-mechanical applications, CSEM's technology of flexure structures and flexible mechanisms is particularly suited to solve many structural and mechanical issues found in such active/adaptive mechanisms. The paper illustrates some recent flexure structures developments at CSEM and outlines the comprehensive know-how involved in this technology. This comprises in particular the elaboration of optimal design guidelines, related to the geometry, kinematics and dynamics issues (for instance, the minimization of spurious high frequency effects), the evaluation and predictability of all performance quantities relevant to the utilization of flexure structures in space (reliability, fatigue, static and dynamic modeling, etc.). material issues and manufacturing procedures.

  3. Activation and Exhaustion of Adaptive Immune Cells in Hepatitis B Infection.

    PubMed

    Gogoi, Dimpu; Borkakoty, Biswajyoti; Biswas, Dipankar; Mahanta, Jagadish

    2015-09-01

    In hepatitis B virus (HBV) infection, the immune reaction is responsible for viral clearance and preventing their spread within the host. However, the immune system is dysfunctional in patients with chronic HBV infection, leading to an inadequate immune response against the virus. A major factor contributing to inefficient immune function is the phenomenon of immune exhaustion. Hence, understanding immune activation and exhaustion during HBV infection is important, as it would provide insight in developing immunotherapy to control chronic HBV infection. The aim of this review is to highlight the existing information on immune effector functions and immune exhaustion in response to HBV infection.

  4. Mechanisms of cell recruitment in the immune response to Mycobacterium tuberculosis.

    PubMed

    Peters, Wendy; Ernst, Joel D

    2003-02-01

    Recent advances in understanding cell traffic, especially the roles of adhesion proteins, chemokines, and chemokine receptors, provide the opportunity for understanding mechanisms involved in the immune response to tuberculosis. This review concentrates on the roles of these molecules and the immune response in tuberculosis, based on studies of humans and mice infected with Mycobacterium tuberculosis.

  5. The role of Toll-like receptors and adaptive immunity in the development of protective or pathological immune response triggered by the Trypanosoma cruzi protozoan.

    PubMed

    Pellegrini, Andrea; Guiñazu, Natalia; Giordanengo, Laura; Cano, Roxana Carolina; Gea, Susana

    2011-12-01

    Trypanosoma cruzi, the causal agent of Chagas disease, is an intracellular protozoan parasite that predominantly invades macrophages and cardiomyocytes, leading to persistent infection. Several members of the Toll-like receptor family are crucial for innate immunity to infection and are involved in maintaining tissue homeostasis. This review focuses on recent experimental findings of the innate and adaptive immune response in controlling the parasite and/or in generating heart and liver tissue injury. We also describe the importance of the host's genetic background in the outcome of the disease and emphasize the importance of studying the response to specific parasite antigens. Understanding the dual participation of the immune response may contribute to the design of new therapies for Chagas disease.

  6. Mechanisms of Borrelia burgdorferi internalization and intracellular innate immune signaling.

    PubMed

    Petnicki-Ocwieja, Tanja; Kern, Aurelie

    2014-01-01

    Lyme disease is a long-term infection whose most severe pathology is characterized by inflammatory arthritis of the lower bearing joints, carditis, and neuropathy. The inflammatory cascades are initiated through the early recognition of invading Borrelia burgdorferi spirochetes by cells of the innate immune response, such as neutrophils and macrophage. B. burgdorferi does not have an intracellular niche and thus much research has focused on immune pathways activated by pathogen recognition molecules at the cell surface, such as the Toll-like receptors (TLRs). However, in recent years, studies have shown that internalization of the bacterium by host cells is an important component of the defense machinery in response to B. burgdorferi. Upon internalization, B. burgdorferi is trafficked through an endo/lysosomal pathway resulting in the activation of a number of intracellular pathogen recognition receptors including TLRs and Nod-like receptors (NLRs). Here we will review the innate immune molecules that participate in both cell surface and intracellular immune activation by B. burgdorferi.

  7. 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.

  8. 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

  9. 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.

  10. T Cell Receptors and the Evolution of Recognition Mechanisms in Immunity.

    ERIC Educational Resources Information Center

    Inchley, C. J.

    1986-01-01

    Discusses recent advances in the study of mammalian immunology. Explains the roles of two families of lymphocytes, the B cells and T cells. Also examines evolutionary mechanisms related to the immune system. (ML)

  11. Webinar Presentation: Towards Understanding the Immune Mechanisms of Air Pollution Associated Asthma

    EPA Pesticide Factsheets

    This presentation, Towards Understanding the Immune Mechanisms of Air Pollution Associated Asthma, was given at the NIEHS/EPA Children's Centers 2015 Webinar Series: Respiratory Health held on Oct. 14, 2015.

  12. Adaptive mechanisms of Campylobacter jejuni to erythromycin treatment

    PubMed Central

    2013-01-01

    Background Macrolide is the drug of choice to treat human campylobacteriosis, but Campylobacter resistance to this antibiotic is rising. The mechanisms employed by Campylobacter jejuni to adapt to erythromycin treatment remain unknown and are examined in this study. The transcriptomic response of C. jejuni NCTC 11168 to erythromycin (Ery) treatment was determined by competitive microarray hybridizations. Representative genes identified to be differentially expressed were further characterized by constructing mutants and assessing their involvement in antimicrobial susceptibility, oxidative stress tolerance, and chicken colonization. Results Following the treatment with an inhibitory dose of Ery, 139 genes were up-regulated and 119 were down-regulated. Many genes associated with flagellar biosynthesis and motility was up-regulated, while many genes involved in tricarboxylic acid cycle, electron transport, and ribonucleotide biosynthesis were down-regulated. Exposure to a sub-inhibitory dose of Ery resulted in differential expression of much fewer genes. Interestingly, two putative drug efflux operons (cj0309c-cj0310c and cj1173-cj1174) were up-regulated. Although mutation of the two operons did not alter the susceptibility of C. jejuni to antimicrobials, it reduced Campylobacter growth under high-level oxygen. Another notable finding is the consistent up-regulation of cj1169c-cj1170c, of which cj1170c encodes a known phosphokinase, an important regulatory protein in C. jejuni. Mutation of the cj1169c-cj1170c rendered C. jejuni less tolerant to atmospheric oxygen and reduced Campylobacter colonization and transmission in chickens. Conclusions These findings indicate that Ery treatment elicits a range of changes in C. jejuni transcriptome and affects the expression of genes important for in vitro and in vivo adaptation. Up-regulation of motility and down-regulation of energy metabolism likely facilitate Campylobacter to survive during Ery treatment. These findings

  13. Automated mechanical ventilation: adapting decision making to different disease states.

    PubMed

    Lozano-Zahonero, S; Gottlieb, D; Haberthür, C; Guttmann, J; Möller, K

    2011-03-01

    The purpose of the present study is to introduce a novel methodology for adapting and upgrading decision-making strategies concerning mechanical ventilation with respect to different disease states into our fuzzy-based expert system, AUTOPILOT-BT. The special features are: (1) Extraction of clinical knowledge in analogy to the daily routine. (2) An automated process to obtain the required information and to create fuzzy sets. (3) The controller employs the derived fuzzy rules to achieve the desired ventilation status. For demonstration this study focuses exclusively on the control of arterial CO(2) partial pressure (p(a)CO(2)). Clinical knowledge from 61 anesthesiologists was acquired using a questionnaire from which different disease-specific fuzzy sets were generated to control p(a)CO(2). For both, patients with healthy lung and with acute respiratory distress syndrome (ARDS) the fuzzy sets show different shapes. The fuzzy set "normal", i.e., "target p(a)CO(2) area", ranges from 35 to 39 mmHg for healthy lungs and from 39 to 43 mmHg for ARDS lungs. With the new fuzzy sets our AUTOPILOT-BT reaches the target p(a)CO(2) within maximal three consecutive changes of ventilator settings. Thus, clinical knowledge can be extended, updated, and the resulting mechanical ventilation therapies can be individually adapted, analyzed, and evaluated.

  14. Adaptive midlife defense mechanisms and late-life health.

    PubMed

    Malone, Johanna C; Cohen, Shiri; Liu, Sabrina R; Vaillant, George E; Waldinger, Robert J

    2013-07-01

    A growing body of research suggests that personality characteristics relate to physical health; however, this relation ship has primarily been tested in cross-sectional studies that have not followed the participants into old age. The present study utilizes data from a 70-year longitudinal study to prospectively examine the relationship between the adaptive defense mechanisms in midlife and objectively assessed physical health in late life. In addition to examining the direct effect, we test whether social support mediates this relation ship. The sample consisted of 90 men who were followed for over seven decades beginning in late adolescence. Health ratings from medical records were made at three time points (ages 70, 75, and 80). Defense mechanisms were coded from narratives by trained independent raters (Vaillant, Bond, & Vaillant, 1986). Independent raters assessed social supports between ages 50 and 70. More adaptive defenses in midlife were associated with better physical health at all three time points in late life. These relationships were partially mediated by social support. Findings are consistent with the theory that defense maturity is important for building social relationships, which in turn contribute to better late-life physical health. Psychological interventions aimed at improving these domains may be beneficial for physical health.

  15. Mucosal Innate and Adaptive Immune Responses against Herpes Simplex Virus Type 2 in a Humanized Mouse Model▿

    PubMed Central

    Kwant-Mitchell, Amanda; Ashkar, Ali A.; Rosenthal, Kenneth L.

    2009-01-01

    Genital herpes, caused by herpes simplex virus type 2 (HSV-2), is one of the most prevalent sexually transmitted diseases worldwide and a risk factor for acquiring human immunodeficiency virus. Although many vaccine candidates have shown promising results in animal models, they have failed to be effective in human trials. In this study, a humanized mouse strain was evaluated as a potential preclinical model for studying human immune responses to HSV-2 infection and vaccination. Immunodeficient mouse strains were examined for their abilities to develop human innate and adaptive immune cells after transplantation of human umbilical cord stem cells. A RAG2−/− γc−/− mouse strain with a BALB/c background was chosen as the most appropriate model and was then examined for its ability to mount innate and adaptive immune responses to intravaginal HSV-2 infection and immunization. After primary infection, human cells in the lymph nodes were able to generate a protective innate immune response and produce gamma interferon (IFN-γ). After intravaginal immunization and infection, human T cells and NK cells were found in the genital tract and iliac lymph nodes. In addition, human T cells in the spleen, lymph nodes, and vaginal tract were able to respond to stimulation with HSV-2 antigens by replicating and producing IFN-γ. Human B cells were also able to produce HSV-2-specific immunoglobulin G. These adaptive responses were also shown to be protective and reduce local viral replication in the genital tract. This approach provides a means for studying human immune responses in vivo using a small-animal model and may become an important preclinical tool. PMID:19656896

  16. Mechanisms of innate immunity in C. elegans epidermis

    PubMed Central

    Taffoni, Clara; Pujol, Nathalie

    2015-01-01

    The roundworm C. elegans has been successfully used for more than 50 y as a genetically tractable invertebrate model in diverse biological fields such as neurobiology, development and interactions. C. elegans feeds on bacteria and can be naturally infected by a wide range of microorganisms, including viruses, bacteria and fungi. Most of these pathogens infect C. elegans through its gut, but some have developed ways to infect the epidermis. In this review, we will mainly focus on epidermal innate immunity, in particular the signaling pathways and effectors activated upon wounding and fungal infection that serve to protect the host. We will discuss the parallels that exist between epidermal innate immune responses in nematodes and mammals. PMID:26716073

  17. The bifacial role of helminths in cancer: involvement of immune and non-immune mechanisms.

    PubMed

    Oikonomopoulou, Katerina; Brinc, Davor; Hadjisavvas, Andreas; Christofi, Georgios; Kyriacou, Kyriacos; Diamandis, Eleftherios P

    2014-06-01

    Infectious agents have been associated with cancer due to activation of pro-carcinogenic inflammatory processes within their host. Several reports, however, indicate that specific pathogens may be able to elicit anti-tumor immune responses that can lead to protection from tumorigenesis or cancer regression. Amongst these "beneficial" pathogens are some helminthic parasites that have already been connected with prevention of autoimmune diseases and allergies, immune conditions increasingly associated with cancer. Even though helminths have co-existed with humans and their ancestors for millions of years, investigations of their impact on human (patho)physiology are relatively new and the functions of components that can explain the helminth bi-directional influence on carcinogenesis are not well understood. This review aims to discuss evidence for the helminth-induced immune, genetic, epigenetic, proteomic, hormonal and metabolic changes that may ultimately mediate the potential pro- or anti-carcinogenic role of helminths. This overview may serve future investigations in clarifying the tumorigenic role of the most common helminthic parasites. It may also inspire the development of anti-cancer regimens and vaccines, in parallel to ongoing efforts of using helminth-based components for the prevention and/or treatment of autoimmune diseases and allergies.

  18. Radiation-induced immune responses: mechanisms and therapeutic perspectives

    PubMed Central

    Jeong, Hoibin; Bok, Seoyeon; Hong, Beom-Ju; Choi, Hyung-Seok

    2016-01-01

    Recent advancement in the radiotherapy technology has allowed conformal delivery of high doses of ionizing radiation precisely to the tumors while sparing large volume of the normal tissues, which have led to better clinical responses. Despite this technological advancement many advanced tumors often recur and they do so within the previously irradiated regions. How could tumors recur after receiving such high ablative doses of radiation? In this review, we outlined how radiation can elicit anti-tumor responses by introducing some of the cytokines that can be induced by ionizing radiation. We then discuss how tumor hypoxia, a major limiting factor responsible for failure of radiotherapy, may also negatively impact the anti-tumor responses. In addition, we highlight how there may be other populations of immune cells including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) that can be recruited to tumors interfering with the anti-tumor immunity. Finally, the impact of irradiation on tumor hypoxia and the immune responses according to different radiotherapy regimen is also delineated. It is indeed an exciting time to see that radiotherapy is being combined with immunotherapy in the clinic and we hope that this review can add an excitement to the field. PMID:27722125

  19. Exploiting the Interplay between Innate and Adaptive Immunity to Improve Immunotherapeutic Strategies for Epstein-Barr-Virus-Driven Disorders

    PubMed Central

    Martorelli, Debora; Muraro, Elena; Merlo, Anna; Turrini, Riccardo; Faè, Damiana Antonia; Rosato, Antonio; Dolcetti, Riccardo

    2012-01-01

    The recent demonstration that immunotherapeutic approaches may be clinically effective for cancer patients has renewed the interest for this strategy of intervention. In particular, clinical trials using adoptive T-cell therapies disclosed encouraging results, particularly in the context of Epstein-Barr-virus- (EBV-) related tumors. Nevertheless, the rate of complete clinical responses is still limited, thus stimulating the development of more effective therapeutic protocols. Considering the relevance of innate immunity in controlling both infections and cancers, innovative immunotherapeutic approaches should take into account also this compartment to improve clinical efficacy. Evidence accumulated so far indicates that innate immunity effectors, particularly NK cells, can be exploited with therapeutic purposes and new targets have been recently identified. We herein review the complex interactions between EBV and innate immunity and summarize the therapeutic strategies involving both adaptive and innate immune system, in the light of a fruitful integration between these immunotherapeutic modalities for a better control of EBV-driven tumors. PMID:22319542

  20. Shigella's ways of manipulating the host intestinal innate and adaptive immune system: a tool box for survival?

    PubMed

    Phalipon, Armelle; Sansonetti, Philippe J

    2007-01-01

    Shigella, a Gram-negative invasive enteropathogenic bacterium, causes the rupture, invasion and inflammatory destruction of the human colonic epithelium. This complex and aggressive process accounts for the symptoms of bacillary dysentery. The so-called invasive phenotype of Shigella is linked to expression of a type III secretory system (TTSS) injecting effector proteins into the epithelial cell membrane and cytoplasm, thereby inducing local but massive changes in the cell cytoskeleton that lead to bacterial internalization into non-phagocytic intestinal epithelial cells. The invasive phenotype also accounts for the potent pro-inflammatory capacity of the microorganism. Recent evidence indicates that a large part of the mucosal inflammation is initiated by intracellular sensing of bacterial peptidoglycan by cytosolic leucine-rich receptors of the NOD family, particularly NOD1, in epithelial cells. This causes activation of the nuclear factor kappa B and c-JunNH(2)-terminal-kinase pathways, with interleukin-8 appearing as a major chemokine mediating the inflammatory burst that is dominated by massive infiltration of the mucosa by polymorphonuclear leukocytes. Not unexpectedly, this inflammatory response, which is likely to be very harmful for the invading microbe, is regulated by the bacterium itself. A group of proteins encoded by Shigella, which are injected into target cells by the TTSS, has been recently recognized as a family of potent regulators of the innate immune response. These enzymes target key cellular functions that are essential in triggering the inflammatory response, and more generally defense responses of the intestinal mucosa. This review focuses on the mechanisms employed by Shigella to manipulate the host innate response in order to escape early bacterial killing, thus ensuring establishment of its infectious process. The escape strategies, the possible direct effect of Shigella on B and T lymphocytes, their impact on the development of

  1. Immunization

    MedlinePlus

    ... remembers" the germ and can fight it again. Vaccines contain germs that have been killed or weakened. When given to a healthy person, the vaccine triggers the immune system to respond and thus ...

  2. Immune Escape Mechanisms are Plasmodium's Secret Weapons Foiling the Success of Potent and Persistently Efficacious Malaria Vaccines.

    PubMed

    Farooq, Fouzia; Bergmann-Leitner, Elke S

    2015-12-01

    Despite decades of active research, an efficacious vaccine mediating long-term protection is still not available. This review highlights various mechanisms and the different facets by which the parasites outsmart the immune system. An understanding of how the parasites escape immune recognition and interfere with the induction of a protective immune response that provides sterilizing immunity will be crucial to vaccine design.

  3. Genome analysis of three Pneumocystis species reveals adaptation mechanisms to life exclusively in mammalian hosts

    PubMed Central

    Ma, Liang; Chen, Zehua; Huang, Da Wei; Kutty, Geetha; Ishihara, Mayumi; Wang, Honghui; Abouelleil, Amr; Bishop, Lisa; Davey, Emma; Deng, Rebecca; Deng, Xilong; Fan, Lin; Fantoni, Giovanna; Fitzgerald, Michael; Gogineni, Emile; Goldberg, Jonathan M.; Handley, Grace; Hu, Xiaojun; Huber, Charles; Jiao, Xiaoli; Jones, Kristine; Levin, Joshua Z.; Liu, Yueqin; Macdonald, Pendexter; Melnikov, Alexandre; Raley, Castle; Sassi, Monica; Sherman, Brad T.; Song, Xiaohong; Sykes, Sean; Tran, Bao; Walsh, Laura; Xia, Yun; Yang, Jun; Young, Sarah; Zeng, Qiandong; Zheng, Xin; Stephens, Robert; Nusbaum, Chad; Birren, Bruce W.; Azadi, Parastoo; Lempicki, Richard A.; Cuomo, Christina A.; Kovacs, Joseph A.

    2016-01-01

    Pneumocystis jirovecii is a major cause of life-threatening pneumonia in immunosuppressed patients including transplant recipients and those with HIV/AIDS, yet surprisingly little is known about the biology of this fungal pathogen. Here we report near complete genome assemblies for three Pneumocystis species that infect humans, rats and mice. Pneumocystis genomes are highly compact relative to other fungi, with substantial reductions of ribosomal RNA genes, transporters, transcription factors and many metabolic pathways, but contain expansions of surface proteins, especially a unique and complex surface glycoprotein superfamily, as well as proteases and RNA processing proteins. Unexpectedly, the key fungal cell wall components chitin and outer chain N-mannans are absent, based on genome content and experimental validation. Our findings suggest that Pneumocystis has developed unique mechanisms of adaptation to life exclusively in mammalian hosts, including dependence on the lungs for gas and nutrients and highly efficient strategies to escape both host innate and acquired immune defenses. PMID:26899007

  4. 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

  5. Different genome stability proteins underpin primed and naïve adaptation in E. coli CRISPR-Cas immunity.

    PubMed

    Ivančić-Baće, Ivana; Cass, Simon D; Wearne, Stephen J; Bolt, Edward L

    2015-12-15

    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.

  6. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity.

    PubMed

    Burnette, Byron C; Liang, Hua; Lee, Youjin; Chlewicki, Lukasz; Khodarev, Nikolai N; Weichselbaum, Ralph R; Fu, Yang-Xin; Auh, Sogyong L

    2011-04-01

    The most widely held explanation for the efficacy of local radiotherapy (RT) is based on direct cytotoxicity to cancer cells through the induction of lethal DNA damage. Recent studies have shown that local ablative radiation of established tumors can lead to increased T-cell priming and T-cell-dependent tumor regression, but the underlying mechanism remains unclear. Here, we describe an essential role for type I IFN in local RT-mediated tumor control. We show that ablative RT increases intratumoral production of IFN-β and, more surprisingly, the antitumor effect of RT is abolished in type I IFN nonresponsive hosts. Furthermore, the major target of RT-induced type I IFN is the hematopoietic compartment. RT drastically enhances the cross-priming capacity of tumor-infiltrating dendritic cells (TIDC) from wild-type mice but not type I IFN receptor-deficient mice. The enhanced cross-priming ability of TIDCs after RT was dependent on autocrine production of type I IFNs. By using adenoviral-mediated expression of IFN-β, we show that delivery of exogenous IFN-β into the tumor tissue in the absence of RT is also sufficient to selectively expand antigen-specific T cells leading to complete tumor regression. Our study reveals that local high-dose RT can trigger production of type I IFN that initiates a cascading innate and adaptive immune attack on the tumor.

  7. Complement and Humoral Adaptive Immunity in the Human Choroid Plexus: Roles for Stromal Concretions, Basement Membranes, and Epithelium

    PubMed Central

    Laule, Cornelia; Leung, Esther; Pavlova, Vladimira; Morgan, B. Paul; Esiri, Margaret M.

    2016-01-01

    The choroid plexus (CP) provides a barrier to entry of toxic molecules from the blood into the brain and transports vital molecules into the cerebrospinal fluid. While a great deal is known about CP physiology, relatively little is known about its immunology. Here, we show immunohistochemical data that help define the role of the CP in innate and adaptive humoral immunity. The results show that complement, in the form of C1q, C3d, C9, or C9neo, is preferentially deposited in stromal concretions. In contrast, immunoglobulin (Ig) G (IgG) and IgA are more often found in CP epithelial cells, and IgM is found in either locale. C4d, IgD, and IgE are rarely, if ever, seen in the CP. In multiple sclerosis CP, basement membrane C9 or stromal IgA patterns were common but were not specific for the disease. These findings indicate that the CP may orchestrate the clearance of complement, particularly by deposition in its concretions, IgA and IgG preferentially via its epithelium, and IgM by either mechanism. PMID:26994633

  8. Omics Approaches for the Study of Adaptive Immunity to Staphylococcus aureus and the Selection of Vaccine Candidates

    PubMed Central

    Holtfreter, Silva; Kolata, Julia; Stentzel, Sebastian; Bauerfeind, Stephanie; Schmidt, Frank; Sundaramoorthy, Nandakumar; Bröker, Barbara M.

    2016-01-01

    Staphylococcus aureus is a dangerous pathogen both in hospitals and in the community. Due to the crisis of antibiotic resistance, there is an urgent need for new strategies to combat S. aureus infections, such as vaccination. Increasing our knowledge about the mechanisms of protection will be key for the successful prevention or treatment of S. aureus invasion. Omics technologies generate a comprehensive picture of the physiological and pathophysiological processes within cells, tissues, organs, organisms and even populations. This review provides an overview of the contribution of genomics, transcriptomics, proteomics, metabolomics and immunoproteomics to the current understanding of S. aureus‑host interaction, with a focus on the adaptive immune response to the microorganism. While antibody responses during colonization and infection have been analyzed in detail using immunoproteomics, the full potential of omics technologies has not been tapped yet in terms of T-cells. Omics technologies promise to speed up vaccine development by enabling reverse vaccinology approaches. In consequence, omics technologies are powerful tools for deepening our understanding of the “superbug” S. aureus and for improving its control. PMID:28248221

  9. The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells

    PubMed Central

    Sintes, Jordi; Polentarutti, Nadia; Walland, A. Cooper; Yeiser, John R.; Cunha, Cristina; Lacerda, João F.; Salvatori, Giovanni; Blander, J. Magarian

    2016-01-01

    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

  10. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer.

    PubMed

    Bracci, L; Schiavoni, G; Sistigu, A; Belardelli, F

    2014-01-01

    Conventional anticancer chemotherapy has been historically thought to act through direct killing of tumor cells. This concept stems from the fact that cytotoxic drugs interfere with DNA synthesis and replication. Accumulating evidence, however, indicates that the antitumor activities of chemotherapy also rely on several off-target effects, especially directed to the host immune system, that cooperate for successful tumor eradication. Chemotherapeutic agents stimulate both the innate and adaptive arms of the immune system through several modalities: (i) by promoting specific rearrangements on dying tumor cells, which render them visible to the immune system; (ii) by influencing the homeostasis of the hematopoietic compartment through transient lymphodepletion followed by rebound replenishment of immune cell pools; (iii) by subverting tumor-induced immunosuppressive mechanisms and (iv) by exerting direct or indirect stimulatory effects on immune effectors. Among the indirect ways of immune cell stimulation, some cytotoxic drugs have been shown to induce an immunogenic type of cell death in tumor cells, resulting in the emission of specific signals that trigger phagocytosis of cell debris and promote the maturation of dendritic cells, ultimately resulting in the induction of potent antitumor responses. Here, we provide an extensive overview of the multiple immune-based mechanisms exploited by the most commonly employed cytotoxic drugs, with the final aim of identifying prerequisites for optimal combination with immunotherapy strategies for the development of more effective treatments against cancer.

  11. A genetic mechanism for Tibetan high-altitude adaptation.

    PubMed

    Lorenzo, Felipe R; Huff, Chad; Myllymäki, Mikko; Olenchock, Benjamin; Swierczek, Sabina; Tashi, Tsewang; Gordeuk, Victor; Wuren, Tana; Ri-Li, Ge; McClain, Donald A; Khan, Tahsin M; Koul, Parvaiz A; Guchhait, Prasenjit; Salama, Mohamed E; Xing, Jinchuan; Semenza, Gregg L; Liberzon, Ella; Wilson, Andrew; Simonson, Tatum S; Jorde, Lynn B; Kaelin, William G; Koivunen, Peppi; Prchal, Josef T

    2014-09-01

    Tibetans do not exhibit increased hemoglobin concentration at high altitude. We describe a high-frequency missense mutation in the EGLN1 gene, which encodes prolyl hydroxylase 2 (PHD2), that contributes to this adaptive response. We show that a variant in EGLN1, c.[12C>G; 380G>C], contributes functionally to the Tibetan high-altitude phenotype. PHD2 triggers the degradation of hypoxia-inducible factors (HIFs), which mediate many physiological responses to hypoxia, including erythropoiesis. The PHD2 p.[Asp4Glu; Cys127Ser] variant exhibits a lower K(m) value for oxygen, suggesting that it promotes increased HIF degradation under hypoxic conditions. Whereas hypoxia stimulates the proliferation of wild-type erythroid progenitors, the proliferation of progenitors with the c.[12C>G; 380G>C] mutation in EGLN1 is significantly impaired under hypoxic culture conditions. We show that the c.[12C>G; 380G>C] mutation originated ∼8,000 years ago on the same haplotype previously associated with adaptation to high altitude. The c.[12C>G; 380G>C] mutation abrogates hypoxia-induced and HIF-mediated augmentation of erythropoiesis, which provides a molecular mechanism for the observed protection of Tibetans from polycythemia at high altitude.

  12. Adaptive mechanical properties of topologically interlocking material systems

    NASA Astrophysics Data System (ADS)

    Khandelwal, S.; Siegmund, T.; Cipra, R. J.; Bolton, J. S.

    2015-04-01

    Topologically interlocked material systems are two-dimensional granular crystals created as ordered and adhesion-less assemblies of unit elements of the shape of platonic solids. The assembly resists transverse forces due to the interlocking geometric arrangement of the unit elements. Topologically interlocked material systems yet require an external constraint to provide resistance under the action of external load. Past work considered fixed and passive constraints only. The objective of the present study is to consider active and adaptive external constraints with the goal to achieve variable stiffness and energy absorption characteristics of the topologically interlocked material system through an active control of the in-plane constraint conditions. Experiments and corresponding model analysis are used to demonstrate control of system stiffness over a wide range, including negative stiffness, and energy absorption characteristics. The adaptive characteristics of the topologically interlocked material system are shown to solve conflicting requirements of simultaneously providing energy absorption while keeping loads controlled. Potential applications can be envisioned in smart structure enhanced response characteristics as desired in shock absorption, protective packaging and catching mechanisms.

  13. Immune oppression array elucidating immune escape and survival mechanisms in uveal melanoma

    PubMed Central

    Hou, Fang; Huang, Qi-Ming; Hu, Dan-Ning; Jonas, Jost B.; Wei, Wen-Bin

    2016-01-01

    AIM To examine the genetic profile of primary uveal melanoma (UM) as compared to UM in immune escape. METHODS Dendritic cells (DC) loaded with lysates of UM cells of high metastatic potential were used to stimulate CTLs(CTLs). When CTLs co-cultured with the UM cells, most UM cells could be eliminated. Survival UM cells grew slowly and were considered to be survival variants and examined by a microarray analysis. These differential genes were analyzed further with Venn Diagrams and functions related to immune escape. We additionally examined transcriptional changes of manually selected survival variants of UM cells and of clinical UM samples by quantitative real-time polymerase chain reaction (qRT-PCR), and analyzed the correlation of these expressions and patients' survival. RESULTS Gene expression analyses revealed a marked up-regulation of SLAMF7 and CCL22 and a significant down-regulation of KRT10, FXYD3 and ABCC2. The expression of these genes in the relapsed UM was significantly greater than those in primary UM. UM patients with overexpression of these genes had a shorter survival period as compared with those of their underexpression. CONCLUSION Gene expression, in particular of SLAMF7, CCL22, KRT10, FXYD3 and ABCC2, differed between primary UM cells and survival variants of UM cells. PMID:28003967

  14. Effects of tumor growth on interleukins and circulating immune complexes. Mechanisms of immune unresponsiveness.

    PubMed

    Ravikumar, T; Steele, G; Rodrick, M; Ross, D; Wilson, R; Lahey, S; Wright, D; Munroe, A; King, V

    1984-03-15

    This study delineates the temporal relationship between immune complex formation and tumor growth, and provides one possible explanation for host immunosuppression during tumor growth. The authors have studied serial circulating immune complex (CIC) levels and interleukin (IL) elaboration by peripheral blood cells (IL-1 production by adherent mononuclear cells [AMC]; and IL-2 generation by peripheral blood mononuclear cells [PBMC]) during the growth of syngeneic tumor isografts in an inbred rat model. Male Wistar/Furth (W/Fu) rats were injected, subcutaneously (SC) with 2 X 10(6) W163 ( a dimethylhydrazine [DMH]-induced colon adenocarcinoma) cells into their hind limbs. Serial CIC levels, (measured by the antigen nonspecific polyethylene glycol turbidity assay) and IL-1 and IL-2 production were measured before isografting and weekly thereafter. Progressive local tumor growth occurred for 3 weeks followed by regional lymph node metastases during the fourth week. During local tumor growth, there was a progressive rise in CIC levels (123% rise compared with baseline value; P less than 0.05) which correlated with a fall in both IL-1 and IL-2 generation (r = -0.768). At the time of regional metastasis, the mean CIC levels declined, and there was a further significant decrease in IL production (IL-1 = 0.9% and IL-2 = 10% of controls in tumor bearers). These results show that progressive tumor growth results in decreased IL production by host PBC, and suggest that CIC may be involved in regulating IL generation.

  15. The cytotoxic protease granzyme M is expressed by lymphocytes of both the innate and adaptive immune system.

    PubMed

    de Koning, Pieter J A; Tesselaar, Kiki; Bovenschen, Niels; Colak, Selçuk; Quadir, Razi; Volman, Thomas J H; Kummer, J Alain

    2010-01-01

    The cytotoxic serine protease granzyme M (GrM) is one of the five human granzymes, which are mainly expressed by cytotoxic T lymphocytes and/or NK cells. Upon perforin-dependent entry into a target cell, GrM cleaves specific substrates resulting in the onset of a unique cell death mechanism. However, the role of GrM in pathophysiological conditions is not clear yet. Knowledge of the expression and regulation of GrM by lymphocyte populations is instrumental for a better understanding of the contribution of this unique granzyme in health and disease. Two previous studies demonstrated GrM protein expression by lymphocytes of the innate immune system, i.e., NK cells, NKT cells, and gammadelta T cells, whereas its expression by CD8(+) T cells remained controversial. In the present study, we have investigated the expression and regulation of GrM in lymphocyte subsets in more detail. Flow cytometry analysis with a novel specific antibody against human GrM confirmed high expression of this protease by NK cells, NKT cells, and gammadelta T cells. CD8(+) T cells also expressed GrM and comparing the naive to early effector-memory, to late effector-memory, to effector subset, this expression gradually increased during differentiation. In contrast, CD4(+) T cells hardly expressed GrM. Quantitative PCR analysis for GrM mRNA levels in the diverse lymphocyte sub-populations confirmed the FACS results. GrM protein expression by lymphocyte populations was not significantly affected by a panel of GrB-inducing cytokines, indicating that GrM expression is differentially regulated as compared to GrB. In conclusion, the human cytotoxic protease GrM is, besides by innate immune cells, also expressed by CD8(+) effector T cells, in particular by the differentiated effector CD27(-) CD45RO(-) subset. Our current findings support not only a role for GrM in the innate but also in the adaptive immune response.

  16. Adaptive information interactive mechanism for multi-UAV visual navigation

    NASA Astrophysics Data System (ADS)

    Liu, Hui; Dai, Qionghai

    2012-06-01

    Multi-unmanned aerial vehicle (UAV) cooperative communication for visual navigation has recently generated significant concern. It has large amounts of visual information to be transmitted and processed among UAVs with realtime requirements. And the UAV clusters have self-organized, time-varying and high dynamic characteristics. Considering the above conditions, we propose an adaptive information interactive mechanism (AIIM) for multi-UAV visual navigation. In the mechanism, the function modules for UAV inter-communication interface are designed, the mobility-based link lifetime is established and the information interactive protocol is presented. Thus we combine the mobility of UAVs with the corresponding communication requirements to make effective information interaction for UAVs. Task-oriented distributed control is adopted to improve the collaboration flexibility in the multi-UAV visual navigation system. In order to timely obtain the necessary visual information, each UAV can cooperate with other relevant UAVs which meet some certain terms such as situation, task or environmental conditions. Simulation results are presented to show the validity of the proposed mechanism in terms of end-to-end delay and links stability.

  17. Multiple representations and mechanisms for visuomotor adaptation in young children.

    PubMed

    Tahej, Pierre-Karim; Ferrel-Chapus, Carole; Olivier, Isabelle; Ginhac, Dominique; Rolland, Jean-Pierre

    2012-12-01

    In this study, we utilized transformed spatial mappings to perturb visuomotor integration in 5-yr-old children and adults. The participants were asked to perform pointing movements under five different conditions of visuomotor rotation (from 0° to 180°), which were designed to reveal explicit vs. implicit representations as well as the mechanisms underlying the visual-motor mapping. Several tests allowed us to separately evaluate sensorimotor (i.e., the dynamic dimension of movement) and cognitive (i.e., the explicit representations of target position and the strategies used by the participants) representations of visuo-proprioceptive distortion. Our results indicate that children do not establish representations in the same manner as adults and that children exhibit multiple visuomotor representations. Sensorimotor representations were relatively precise, presumably due to the recovery of proprioceptive information and efferent copy. Furthermore, a bidirectional mechanism was used to re-map visual and motor spaces. In contrast, cognitive representations were supplied with visual information and followed a unidirectional visual-motor mapping. Therefore, it appears that sensorimotor mechanisms develop before the use of explicit strategies during development, and young children showed impaired visuomotor adaptation when confronted with large distortions.

  18. Adaptive antiviral immunity is a determinant of the therapeutic success of oncolytic virotherapy.

    PubMed

    Sobol, Paul T; Boudreau, Jeanette E; Stephenson, Kyle; Wan, Yonghong; Lichty, Brian D; Mossman, Karen L

    2011-02-01

    Oncolytic virotherapy, the selective killing of tumor cells by oncolytic viruses (OVs), has emerged as a promising avenue of anticancer research. We have previously shown that KM100, a Herpes simplex virus type-1 (HSV) deficient for infected cell protein 0 (ICP0), possesses substantial oncolytic properties in vitro and has antitumor efficacy in vivo, in part by inducing antitumor immunity. Here, we illustrate through T-cell immunodepletion studies in nontolerized tumor-associated antigen models of breast cancer that KM100 treatment promotes antiviral and antitumor CD8(+) cytotoxic T-cell responses necessary for complete tumor regression. In tolerized tumor-associated antigen models of breast cancer, antiviral CD8(+) cytotoxic T-cell responses against infected tumor cells correlated with the induction of significant tumoristasis in the absence of tumor-associated antigen-specific CD8(+) cytotoxic T-cells. To enhance oncolysis, we tested a more cytopathic ICP0-null HSV and a vesicular stomatitis virus M protein mutant and found that despite improved in vitro replication, oncolysis in vivo did not improve. These studies illustrate that the in vitro cytolytic properties of OVs are poor prognostic indicators of in vivo antitumor activity, and underscore the importance of adaptive antiviral CD8(+) cytotoxic T-cells in effective cancer virotherapy.

  19. CD22 Regulates Adaptive and Innate Immune Responses of B Cells

    PubMed Central

    Kawasaki, Norihito; Rademacher, Christoph; Paulson, James C.

    2011-01-01

    B cells sense microenvironments through the B cell receptor (BCR) and Toll-like receptors (TLRs). While signals from BCR and TLRs synergize to distinguish self from nonself, inappropriate regulation can result in development of autoimmune disease. Here we show that CD22, an inhibitory co-receptor of BCR, also negatively regulates TLR signaling in B cells. CD22-deficient (Cd22–/–) B cells exhibit hyperactivation in response to ligands of TLRs 3, 4 and 9. Evidence suggests that this results from impaired induction of suppressors of cytokine signaling 1 and 3, well-known suppressors of TLR signaling. Antibody-mediated sequestration of CD22 on wild-type (WT) B cells augments proliferation by TLR ligands. Conversely, expression of CD22 in a Cd22–/– B cell line blunts responses to TLR ligands. We also show that lipopolysaccharide-induced transcription by nuclear factor-κB is inhibited by ectopic expression of CD22 in a TLR4 reporter cell line. Taken together, these results suggest that negative regulation of TLR signaling is an intrinsic property of CD22. Since TLRs and BCR activate B cells through different signaling pathways, and are differentially localized in B cells, CD22 exhibits a broader regulation of receptors that mediate adaptive and innate immune responses of B cells than previously recognized. PMID:21178327

  20. Mechanisms of Cardiopulmonary Adaptation to Microgravity. Part 1

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Session TA1 includes short reports covering: (1) Indices of Baroreceptor Reflex Sensitivity: The Use in Rehabilitation Medicine and Space Cardiology; (2) +Gz and +Gx Tolerance of Healthy Persons of Non-Flying Trades at Primary Selection of the Centrifuge; (3) Effect of Dry Immersion on Calf Blood Supply During Sustained Contraction and Upright Exercise in Man; (4) Cardiovascular and Valsalva Responses during Parabolic flight; (5) An Analysis of the Cardiovascular Responses under Hyper- and Hypo-Gravity Environments using a Mathematical model; (6) Effect of Very Gradual Onset Rate +Gz Exposures on the Cardiovascular System; and (7) NASA Specialized Center of Research and Training (NSCORT) in Integrated Physiology: Mechanisms of Physiological Adaptations to Microgravity.

  1. Adaptive broadcasting mechanism for bandwidth allocation in mobile services.

    PubMed

    Horng, Gwo-Jiun; Wang, Chi-Hsuan; Chou, Chih-Lun

    2014-01-01

    This paper proposes a tree-based adaptive broadcasting (TAB) algorithm for data dissemination to improve data access efficiency. The proposed TAB algorithm first constructs a broadcast tree to determine the broadcast frequency of each data and splits the broadcast tree into some broadcast wood to generate the broadcast program. In addition, this paper develops an analytical model to derive the mean access latency of the generated broadcast program. In light of the derived results, both the index channel's bandwidth and the data channel's bandwidth can be optimally allocated to maximize bandwidth utilization. This paper presents experiments to help evaluate the effectiveness of the proposed strategy. From the experimental results, it can be seen that the proposed mechanism is feasible in practice.

  2. Progesterone-based contraceptives reduce adaptive immune responses and protection against sequential influenza A virus infections.

    PubMed

    Hall, Olivia J; Nachbagauer, Raffael; Vermillion, Meghan S; Fink, Ashley L; Phuong, Vanessa; Krammer, Florian; Klein, Sabra L

    2017-02-08

    In addition to their intended use, progesterone (P4)-based contraceptives promote anti-inflammatory immune responses, yet their effects on the outcome of infectious diseases, including influenza A virus (IAV), are rarely evaluated. To evaluate their impact on immune responses to sequential IAV infections, adult female mice were treated with placebo or one of two progestins, P4 or levonorgestrel (LNG), and infected with mouse adapted (ma) H1N1 virus. Treatment with P4 or LNG reduced morbidity, but had no effect on pulmonary virus titers, during primary H1N1 infection as compared to placebo treatment. In serum and bronchoalveolar lavage fluid, total anti-IAV IgG and IgA titers and virus neutralizing antibody titers, but not hemagglutinin stalk antibody titers, were lower in progestin-treated mice as compared with placebo-treated mice. Females were challenged six weeks later with either a maH1N1 drift variant (maH1N1dv) or maH3N2 IAV. Protection following infection with the maH1N1dv was similar among all groups. In contrast, following challenge with maH3N2, progestin treatment reduced survival as well as numbers and activity of H1N1- and H3N2-specific memory CD8+ T cells, including tissue resident cells, compared with placebo treatment. In contrast to primary IAV infection, progestin treatment increased neutralizing and IgG antibody titers against both challenge viruses compared with placebo treatment. While the immunomodulatory properties of progestins protected naïve females against severe outcome from IAV infection, it made them more susceptible to secondary challenge with a heterologous IAV, despite improving their antibody responses against a secondary IAV infection. Taken together, the immunomodulatory effects of progestins differentially regulate the outcome of infection depending on exposure history.IMPORTANCE The impact of hormone-based contraceptives on the outcome of infectious diseases outside of the reproductive tract is rarely considered. Using a mouse

  3. 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

  4. Immune mechanisms regulating pharmacokinetics and pharmacodynamics of PEGylated liposomal anticancer agents

    NASA Astrophysics Data System (ADS)

    Song, Gina

    Nanotechnology has made significant advances in drug delivery system for the treatment of cancer. Among various nanoparticle (NP) platforms, liposomes have been most widely used as a NP drug carrier for cancer therapy. High variation in pharmacokinetics (PK) and pharmacodynamics (PD) of liposome-based therapeutics has been reported. However, the interaction of liposome-based therapeutics with the immune system, specifically the mononuclear phagocyte system (MPS), and underlying molecular mechanisms for variable responses to liposomal drugs remain poorly understood. The objective of this dissertation was to elucidate immune mechanisms for the variable responses to PEGylated liposomal doxorubicin (PLD; DoxilRTM), a clinically relevant NP, in animal models and in patients. In vitro, in vivo and clinical systems were investigated to evaluate the effects of chemokines (CCL2 and CCL5), heterogeneity of the tumor microenvironment, and genetic variations on PK and PD of PLD. Results showed that there was a significantly positive linear relationship between PLD exposure (AUC) and total amount of CCL2 and CCL5, most prevalent chemokines in plasma, in patients with recurrent ovarian cancer. Consistent with these findings, preclinical studies using mice bearing SKOV3 orthotopic ovarian cancer xenografts demonstrated that PLD induced the production and secretion of chemokines into plasma. In addition, in vitro studies using human monocytic THP-1 cells demonstrated that PLD altered monocyte migration towards CCL2 and CCL5. The PK and efficacy studies of PLD in murine models of breast cancer showed that heterogeneous tumor microenvironment was associated with significantly different tumor delivery and efficacy of PLD, but not small molecule doxorubicin between two breast tumor models. A candidate genetic locus that was associated with clearance of PLD in 23 inbred mouse strains contains a gene that encodes for engulfment adapter PTB domain containing 1 (Gulp1). By using

  5. Interferon-inducible effector mechanisms in cell-autonomous immunity.

    PubMed

    MacMicking, John D

    2012-04-25

    Interferons (IFNs) induce the expression of hundreds of genes as part of an elaborate antimicrobial programme designed to combat infection in all nucleated cells - a process termed cell-autonomous immunity. As described in this Review, recent genomic and subgenomic analyses have begun to assign functional properties to novel IFN-inducible effector proteins that restrict bacteria, protozoa and viruses in different subcellular compartments and at different stages of the pathogen life cycle. Several newly described host defence factors also participate in canonical oxidative and autophagic pathways by spatially coordinating their activities to enhance microbial killing. Together, these IFN-induced effector networks help to confer vertebrate host resistance to a vast and complex microbial world.

  6. Immune and Inflammatory Mechanisms in Pulmonary Arterial Hypertension

    PubMed Central

    El Chami, Hala; Hassoun, Paul M.

    2012-01-01

    Altered immunity and inflammation are increasingly recognized features of pulmonary arterial hypertension (PAH). This is suggested by infiltration of various inflammatory cells (e.g., macrophages, T and B lymphocytes), increased cytokine and growth factor (e.g., VEGF and PDGF) expression in remodeled pulmonary vessels, and the presence of circulating chemokines and cytokines. In certain diseases associated with PAH, increased expression of growth and transcriptional (e.g., Nuclear Factor of Activated T cells or NFAT) factors, and viral protein components (e.g., HIV-1 Nef), appear to contribute directly to recruitment of inflammatory cells in remodeled vessels, and may potentially serve as specific therapeutic targets. This section provides an overview of inflammatory pathways highlighting their potential role in pulmonary vascular remodeling in PAH and the possibility of future targeted therapy. PMID:23009917

  7. TNF-alpha blockade by a dimeric TNF type I receptor molecule selectively inhibits adaptive immune responses.

    PubMed

    Colagiovanni, D B; Suniga, M A; Frazier, J L; Edwards, C K; Fleshner, M; McCay, J A; White, K L; Shopp, G M

    2000-11-01

    Tumor necrosis factor-alpha (TNF-alpha) is a mediator of severe inflammatory processes, including rheumatoid arthritis. Suppression of TNF with a soluble type I or type II receptor molecule (TNF-RI or TNF-RII) has the potential to decrease cytokine levels and modulate inflammatory diseases in humans. However, it has recently been reported that treatment of mice with a TNF-RI:Fc immunoadhesin protein augmented Gram positive infections and subsequent mortality. To determine if TNF-alpha blockade with soluble TNF-alpha receptors might alter immune system function, assays were assessed in rodents treated with a dimeric form of the p55 TNF-RI, Tumor Necrosis Factor-binding protein (TNFbp). Administration of TNFbp resulted in suppression of primary and secondary IgG antibody responses and cell-mediated immune function. No treatment-related differences were detected in immune-enhancing assays or non-specific immune function parameters. Bacterial host resistance assays with Listeria monocytogenes, Staphylococcus aureus or Escherichia coli showed an increase in tissue colony counts only with L. monocytogenes challenged animals following TNFbp administration. These results suggest that TNFbp has the capacity to inhibit adaptive immune function in experimental animal models. Studies suggest that while reducing TNF-alpha is important in controlling cytokine-dependent disease states, maintenance of a threshold level may be critical for normal immune function.

  8. Block-adaptive quantum mechanics: an adaptive divide-and-conquer approach to interactive quantum chemistry.

    PubMed

    Bosson, Maël; Grudinin, Sergei; Redon, Stephane

    2013-03-05

    We present a novel Block-Adaptive Quantum Mechanics (BAQM) approach to interactive quantum chemistry. Although quantum chemistry models are known to be computationally demanding, we achieve interactive rates by focusing computational resources on the most active parts of the system. BAQM is based on a divide-and-conquer technique and constrains some nucleus positions and some electronic degrees of freedom on the fly to simplify the simulation. As a result, each time step may be performed significantly faster, which in turn may accelerate attraction to the neighboring local minima. By applying our approach to the nonself-consistent Atom Superposition and Electron Delocalization Molecular Orbital theory, we demonstrate interactive rates and efficient virtual prototyping for systems containing more than a thousand of atoms on a standard desktop computer.

  9. Inactivated Influenza Vaccine That Provides Rapid, Innate-Immune-System-Mediated Protection and Subsequent Long-Term Adaptive Immunity

    PubMed Central

    Wong, Chinn Yi; Mifsud, Edin J.; Edenborough, Kathryn M.; Sekiya, Toshiki; Tan, Amabel C. L.; Mercuri, Francesca; Rockman, Steve; Chen, Weisan; Turner, Stephen J.; Doherty, Peter C.; Kelso, Anne; Brown, Lorena E.; Jackson, David C.

    2015-01-01

    ABSTRACT The continual threat to global health posed by influenza has led to increased efforts to improve the effectiveness of influenza vaccines for use in epidemics and pandemics. We show in this study that formulation of a low dose of inactivated detergent-split influenza vaccine with a Toll-like receptor 2 (TLR2) agonist-based lipopeptide adjuvant (R4Pam2Cys) provides (i) immediate, antigen-independent immunity mediated by the innate immune system and (ii) significant enhancement of antigen-dependent immunity which exhibits an increased breadth of effector function. Intranasal administration of mice with vaccine formulated with R4Pam2Cys but not vaccine alone provides protection against both homologous and serologically distinct (heterologous) viral strains within a day of administration. Vaccination in the presence of R4Pam2Cys subsequently also induces high levels of systemic IgM, IgG1, and IgG2b antibodies and pulmonary IgA antibodies that inhibit hemagglutination (HA) and neuraminidase (NA) activities of homologous but not heterologous virus. Improved primary virus nucleoprotein (NP)-specific CD8+ T cell responses are also induced by the use of R4Pam2Cys and are associated with robust recall responses to provide heterologous protection. These protective effects are demonstrated in wild-type and antibody-deficient animals but not in those depleted of CD8+ T cells. Using a contact-dependent virus transmission model, we also found that heterologous virus transmission from vaccinated mice to naive mice is significantly reduced. These results demonstrate the potential of adding a TLR2 agonist to an existing seasonal influenza vaccine to improve its utility by inducing immediate short-term nonspecific antiviral protection and also antigen-specific responses to provide homologous and heterologous immunity. PMID:26507227

  10. 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…

  11. Effector Mechanisms of Protection against Pseudomonas aeruginosa Keratitis in Immunized Rats

    PubMed Central

    Thakur, A.; Kyd, J.; Xue, M.; Willcox, M. D. P.; Cripps, A.

    2001-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen which causes sight-threatening corneal infections in humans. The purpose of this study was to evaluate various immunization routes that may provide protection against Pseudomonas keratitis and to define the molecular mechanisms involved in the protection. Sprague-Dawley rats (10 to 12 weeks old) were immunized using paraformaldehyde-killed P. aeruginosa (strain 6206) via oral, nasal, and intra-Peyer's patch (IPP) routes followed by an ocular topical booster dose. Scratched corneas were challenged with an infective dose of P. aeruginosa. Following clinical examination, eyes were enucleated for histology, polymorphonuclear leukocyte (PMN) quantitation, bacterial count, enzyme-linked immunosorbent assay, and RNase protection assay. PMN infiltration was higher early (4 h) during the infection in immunized rats than in nonimmunized rats. Later during the infection, the number of PMNs diminished in immunized rats while in nonimmunized animals the number of PMNs continued to increase. Bacteria were cleared much faster from immunized groups than from the nonimmunized group, and the nasally immunized group had the most efficacious response among the immunized groups. Nasal and IPP immunization groups had increased cytokine expression of interleukin-2 (IL-2) and IL-5 and differed from each other for IL-6. All three immunized groups had significantly reduced IL-1β levels when compared with the nonimmunized rats and a significantly altered profile for CINC-1 expression. This study has shown that the route of immunization modulates the inflammatory response to ocular P. aeruginosa infection, thus affecting the severity of keratitis and adverse pathology, with nasal immunization being the most effective. PMID:11292752

  12. Identification and utility of innate immune system evasion mechanisms of ASFV.

    PubMed

    Correia, Sílvia; Ventura, Sónia; Parkhouse, Robert Michael

    2013-04-01

    The interferon (IFN) system is an early innate anti-virus host defense mechanism that takes place shortly after entry of the pathogen and long before the onset of adaptive immunity. Thus, African swine fever virus (ASFV), as an acute and persistent virus in pigs, is predicted to have evolved multiple genes for the manipulation and evasion of interferon. Although, ASFV is known to interfere with signaling pathways controlling the transcription of cytokines, surprisingly no individual virus gene manipulating the induction or impact of IFN has been described. Since an initial bioinformatics search of the ASFV genome failed to identify potential antagonists of the IFN response, our strategy was to functionally screen early expressed, "unassigned" ASFV genes without existing homologies, particularly from MGFs 360 and 530, in luciferase reporter assays for their inhibition of the induction and impact of IFN. Specifically, we used reporter plasmids containing the luciferase gene under the control of: (1) the IFN-β promoter, to screen for inhibition of induction of type I IFN stimulated by the addition of Poly(I:C); (2) the ISRE DNA elements, to screen for the inhibition of the impact of type I IFN; and (3) the GAS DNA elements to screen for the inhibition of the impact of type II IFN. Our initial experiments revealed six ASFV genes inhibiting one or more of the three luciferase assays. From these, we have selected a total of 3 genes for presentation. The ASFV A276R gene from MGF360 inhibited the induction of IFN-β via both the TLR3 and the cytosolic pathways, targeting IRF3, but not IRF7 or NF-κB. The ASFV A528R inhibited the induction of both NF-κB and IRF3 branches of the type I IFN induction signaling pathway and the impact of IFN response via both IFN type I and type II stimulation. The ASFV I329L gene is a functional viral TLR3 homologue inhibiting the induction of IFN at the level of TRIF. Thus, these genes reduce the IFN response by targeting different

  13. 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

  14. [Heart failure due to ischemia--the adaptive mechanisms].

    PubMed

    Mitu, M; Mitu, F

    1999-01-01

    Chronic myocardial ischemia is the leading cause of disturbances in myocardial contractility (myocardial infarction) or hemodynamic overload upon the left ventricle. The heart reactions consist in a series of adaptative mechanisms in order to maintain its pump function: Frank-Starling mechanism, myocardial hypertrophy and neurohumoral activation. In heart failure, the cardiac output is maintained by an increase of the preload which enhances the contractility (Frank-Starling law). Myocardial ischemia influences the systolic and diastolic function. The decrease of cardiac output leads to neurohumoral responses which, in the initial stages of cardiac failure are compensatory; along with the progression of the disease, they exert adverse effects. Increased activity of the sympathetic nervous system induces high cardiac rates, chronotropic incompetence. Activation of the renin-angiotensin system held to myocardial and vascular hypertrophy, vasoconstriction, fluid retention. Endothelin is the most powerful vasoconstrictor; its plasmatic concentrations correlate with the severity of the disease. Vasodilator mediators released in cardiac failure are the natriuretic peptide, nitric oxide, dopamine, prostacicline, bradikinin.

  15. Molecular mechanisms of Tetranychus urticae chemical adaptation in hop fields

    PubMed Central

    Piraneo, Tara G.; Bull, Jon; Morales, Mariany A.; Lavine, Laura C.; Walsh, Douglas B.; Zhu, Fang

    2015-01-01

    The two-spotted spider mite, Tetranychus urticae Koch is a major pest that feeds on >1,100 plant species. Many perennial crops including hop (Humulus lupulus) are routinely plagued by T. urticae infestations. Hop is a specialty crop in Pacific Northwest states, where 99% of all U.S. hops are produced. To suppress T. urticae, growers often apply various acaricides. Unfortunately T. urticae has been documented to quickly develop resistance to these acaricides which directly cause control failures. Here, we investigated resistance ratios and distribution of multiple resistance-associated mutations in field collected T. urticae samples compared with a susceptible population. Our research revealed that a mutation in the cytochrome b gene (G126S) in 35% tested T. urticae populations and a mutation in the voltage-gated sodium channel gene (F1538I) in 66.7% populations may contribute resistance to bifenazate and bifenthrin, respectively. No mutations were detected in Glutamate-gated chloride channel subunits tested, suggesting target site insensitivity may not be important in our hop T. urticae resistance to abamectin. However, P450-mediated detoxification was observed and is a putative mechanism for abamectin resistance. Molecular mechanisms of T. urticae chemical adaptation in hopyards is imperative new information that will help growers develop effective and sustainable management strategies. PMID:26621458

  16. Adjunct Strategies for Tuberculosis Vaccines: Modulating Key Immune Cell Regulatory Mechanisms to Potentiate Vaccination

    PubMed Central

    Jayashankar, Lakshmi; Hafner, Richard

    2016-01-01

    Tuberculosis (TB) remains a global health threat of alarming proportions, resulting in 1.5 million deaths worldwide. The only available licensed vaccine, Bacillus Calmette–Guérin, does not confer lifelong protection against active TB. To date, development of an effective vaccine against TB has proven to be elusive, and devising newer approaches for improved vaccination outcomes is an essential goal. Insights gained over the last several years have revealed multiple mechanisms of immune manipulation by Mycobacterium tuberculosis (Mtb) in infected macrophages and dendritic cells that support disease progression and block development of protective immunity. This review provides an assessment of the known immunoregulatory mechanisms altered by Mtb, and how new interventions may reverse these effects. Examples include blocking of inhibitory immune cell coreceptor checkpoints (e.g., programed death-1). Conversely, immune mechanisms that strengthen immune cell effector functions may be enhanced by interventions, including stimulatory immune cell coreceptors (e.g., OX40). Modification of the activity of key cell “immunometabolism” signaling pathway molecules, including mechanistic target of rapamycin, glycogen synthase kinase-3β, wnt/β-catenin, adenosine monophosophate-activated protein kinase, and sirtuins, related epigenetic changes, and preventing induction of immune regulatory cells (e.g., regulatory T cells, myeloid-derived suppressor cells) are powerful new approaches to improve vaccine responses. Interventions to favorably modulate these components have been studied primarily in oncology to induce efficient antitumor immune responses, often by potentiation of cancer vaccines. These agents include antibodies and a rapidly increasing number of small molecule drug classes that have contributed to the dramatic immune-based advances in treatment of cancer and other diseases. Because immune responses to malignancies and to Mtb share many similar mechanisms

  17. Lipocalin 2 bolsters innate and adaptive immune responses to blood-stage malaria infection by reinforcing host iron metabolism.

    PubMed

    Zhao, Hong; Konishi, Aki; Fujita, Yukiko; Yagi, Masanori; Ohata, Keiichi; Aoshi, Taiki; Itagaki, Sawako; Sato, Shintaro; Narita, Hirotaka; Abdelgelil, Noha H; Inoue, Megumi; Culleton, Richard; Kaneko, Osamu; Nakagawa, Atsushi; Horii, Toshihiro; Akira, Shizuo; Ishii, Ken J; Coban, Cevayir

    2012-11-15

    Plasmodium parasites multiply within host erythrocytes, which contain high levels of iron, and parasite egress from these cells results in iron release and host anemia. Although Plasmodium requires host iron for replication, how host iron homeostasis and responses to these fluxes affect Plasmodium infection are incompletely understood. We determined that Lipocalin 2 (Lcn2), a host protein that sequesters iron, is abundantly secreted during human (P. vivax) and mouse (P. yoeliiNL) blood-stage malaria infections and is essential to control P. yoeliiNL parasitemia, anemia, and host survival. During infection, Lcn2 bolsters both host macrophage function and granulocyte recruitment and limits reticulocytosis, or the expansion of immature erythrocytes, which are the preferred target cell of P. yoeliiNL. Additionally, a chronic iron imbalance due to Lcn2 deficiency results in impaired adaptive immune responses against Plasmodium parasites. Thus, Lcn2 exerts antiparasitic effects by maintaining iron homeostasis and promoting innate and adaptive immune responses.

  18. Diminished Innate Antiviral Response to Adenovirus Vectors in cGAS/STING-Deficient Mice Minimally Impacts Adaptive Immunity

    PubMed Central

    Anghelina, Daniela; Lam, Eric

    2016-01-01

    ABSTRACT Infection by adenovirus, a nonenveloped DNA virus, induces antiviral innate and adaptive immune responses. Studies of transformed human and murine cell lines using short hairpin RNA (shRNA) knockdown strategies identified cyclic guanine adenine synthase (cGAS) as a pattern recognition receptor (PRR) that contributes to the antiadenovirus response. Here we demonstrate how the cGAS/STING cascade influences the antiviral innate and adaptive immune responses in a murine knockout model. Using knockout bone marrow-derived dendritic cells (BMDCs) and bone marrow-derived macrophages (BMMOs), we determined that cGAS and STING are essential to the induction of the antiadenovirus response in these antigen-presenting cells (APCs) in vitro. We next determined how the cGAS/STING cascade impacts the antiviral response following systemic administration of a recombinant adenovirus type 5 vector (rAd5V). Infection of cGAS−/− and STING−/− mice results in a compromised early antiviral innate response compared to that in wild-type (WT) controls: significantly lower levels of beta interferon (IFN-β) secretion, low levels of proinflammatory chemokine induction, and reduced levels of antiviral transcript induction in hepatic tissue. At 24 h postinfection, levels of viral DNA and reporter gene expression in the liver were similar in all strains. At 28 days postinfection, clearance of infected hepatocytes in cGAS or STING knockout mice was comparable to that in WT C57BL/6 mice. Levels of neutralizing anti-Ad5V antibody were modestly reduced in infected cGAS mice. These data support a dominant role for the cGAS/STING cascade in the early innate antiviral inflammatory response to adenovirus vectors. However, loss of the cGAS/STING pathway did not affect viral clearance, and cGAS deficiency had a modest influence on the magnitude of the antiviral humoral immune response to adenovirus infections. IMPORTANCE The detection of viral infection by host sentinel immune cells

  19. AID can restrict L1 retrotransposition suggesting a dual role in innate and adaptive immunity.

    PubMed

    MacDuff, Donna A; Demorest, Zachary L; Harris, Reuben S

    2009-04-01

    Retrotransposons make up over 40% of the mammalian genome. Some copies are still capable of mobilizing and new insertions promote genetic variation. Several members of the APOBEC3 family of DNA cytosine deaminases function to limit the replication of a variety of retroelements, such as the long-terminal repeat (LTR)-containing MusD and Ty1 elements, and that of the non-LTR retrotransposons, L1 and Alu. However, the APOBEC3 genes are limited to mammalian lineages, whereas retrotransposons are far more widespread. This raises the question of what cellular factors control retroelement transposition in species that lack APOBEC3 genes. A strong phylogenetic case can be made that an ancestral activation-induced deaminase (AID)-like gene duplicated and diverged to root the APOBEC3 lineage in mammals. Therefore, we tested the hypothesis that present-day AID proteins possess anti-retroelement activity. We found that AID can inhibit the retrotransposition of L1 through a DNA deamination-independent mechanism. This mechanism may manifest in the cytoplasmic compartment co- or posttranslationally. Together with evidence for AID expression in the ovary, our data combined to suggest that AID has innate immune functions in addition to its integral roles in creating antibody diversity.

  20. Metabolic and adaptive immune responses induced in mice infected with tissue-dwelling nematode Trichinella zimbabwensis

    PubMed Central

    Onkoba, N.; Chimbari, M.J.; Kamau, J.M.; Mukaratirwa, S.

    2016-01-01

    Tissue-dwelling helminths are known to induce intestinal and systemic inflammation accompanied with host compensatory mechanisms to counter balance nutritional and metabolic deficiencies. The metabolic and immune responses of the host depend on parasite species and tissues affected by the parasite. This study investigated metabolic and immuno-inflammatory responses of mice infected with tissue-dwelling larvae of Trichinella zimbabwensis and explored the relationship between infection, metabolic parameters and Th1/Th17 immune responses. Sixty (60) female BALB/c mice aged between 6 to 8 weeks old were randomly assigned into T. zimbabwensis-infected and control groups. Levels of Th1 (interferon-γ) and Th17 (interleukin-17) cytokines, insulin and blood glucose were determined as well as measurements of body weight, food and water intake. Results showed that during the enteric phase of infection, insulin and IFN-γ levels were significantly higher in the Trichinella infected group accompanied with a reduction in the trends of food intake and weight loss compared with the control group. During systemic larval migration, trends in food and water intake were significantly altered and this was attributed to compensatory feeding resulting in weight gain, reduced insulin levels and increased IL-17 levels. Larval migration also induced a Th1/Th17 derived inflammatory response. It was concluded that T. zimbabwensis alters metabolic parameters by instigating host compensatory feeding. Furthermore, we showed for the first time that non-encapsulated T. zimbabwensis parasite plays a role in immunomodulating host Th1/Th17 type responses during chronic infection. PMID:27882304

  1. 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

  2. Adaptive immune response in JAM-C-deficient mice: normal initiation but reduced IgG memory.

    PubMed

    Zimmerli, Claudia; Lee, Boris P L; Palmer, Gaby; Gabay, Cem; Adams, Ralf; Aurrand-Lions, Michel; Imhof, Beat A

    2009-04-15

    We have recently shown that junctional adhesion molecule (JAM)-C-deficient mice have leukocytic pulmonary infiltrates, disturbed neutrophil homeostasis, and increased postnatal mortality. This phenotype was partially rescued when mice were housed in ventilated isolators, suggesting an inability to cope with opportunistic infections. In the present study, we further examined the adaptive immune responses in JAM-C(-/-) mice. We found that murine conventional dendritic cells express in addition to Mac-1 and CD11c also JAM-B as ligand for JAM-C. By in vitro adhesion assay, we show that murine DCs can interact with recombinant JAM-C via Mac-1. However, this interaction does not seem to be necessary for dendritic cell migration and function in vivo, even though JAM-C is highly expressed by lymphatic sinuses of lymph nodes. Nevertheless, upon immunization and boosting with a protein Ag, JAM-C-deficient mice showed decreased persistence of specific circulating Abs although the initial response was normal. Such a phenotype has also been observed in a model of Ag-induced arthritis, showing that specific IgG2a Ab titers are reduced in the serum of JAM-C(-/-) compared with wild-type mice. Taken together, these data suggest that JAM-C deficiency affects the adaptive humoral immune response against pathogens, in addition to the innate immune system.

  3. Molecular interaction between natural IgG and ficolin - mechanistic insights on adaptive-innate immune crosstalk

    NASA Astrophysics Data System (ADS)

    Panda, Saswati; Zhang, Jing; Yang, Lifeng; Anand, Ganesh S.; Ding, Jeak L.

    2014-01-01

    Recently, we found that natural IgG (nIgG; a non-specific immunoglobulin of adaptive immunity) is not quiescent, but plays a crucial role in immediate immune defense by collaborating with ficolin (an innate immune protein). However, how the nIgG and ficolin interplay and what factors control the complex formation during infection is unknown. Here, we found that mild acidosis and hypocalcaemia induced by infection- inflammation condition increased the nIgG:ficolin complex formation. Hydrogen-deuterium exchange mass spectrometry delineated the binding interfaces to the CH2-CH3 region of nIgG Fc and P-subdomain of ficolin FBG domain. Infection condition exposes novel binding sites. Site-directed mutagenesis and surface plasmon resonance analyses of peptides, derived from nIgG and ficolin, defined the interacting residues between the proteins. These results provide mechanistic insights on the interaction between two molecules representing the adaptive and innate immune pathways, prompting potential development of immunomodulatory/prophylactic peptides tunable to prevailing infection conditions.

  4. Integrated physiological mechanisms of exercise performance, adaptation, and maladaptation to heat stress.

    PubMed

    Sawka, Michael N; Leon, Lisa R; Montain, Scott J; Sonna, Larry A

    2011-10-01

    This article emphasizes significant recent advances regarding heat stress and its impact on exercise performance, adaptations, fluid electrolyte imbalances, and pathophysiology. During exercise-heat stress, the physiological burden of supporting high skin blood flow and high sweating rates can impose considerable cardiovascular strain and initiate a cascade of pathophysiological events leading to heat stroke. We examine the association between heat stress, particularly high skin temperature, on diminishing cardiovascular/aerobic reserves as well as increasing relative intensity and perceptual cues that degrade aerobic exercise performance. We discuss novel systemic (heat acclimation) and cellular (acquired thermal tolerance) adaptations that improve performance in hot and temperate environments and protect organs from heat stroke as well as other dissimilar stresses. We delineate how heat stroke evolves from gut underperfusion/ischemia causing endotoxin release or the release of mitochondrial DNA fragments in response to cell necrosis, to mediate a systemic inflammatory syndrome inducing coagulopathies, immune dysfunction, cytokine modulation, and multiorgan damage and failure. We discuss how an inflammatory response that induces simultaneous fever and/or prior exposure to a pathogen (e.g., viral infection) that deactivates molecular protective mechanisms interacts synergistically with the hyperthermia of exercise to perhaps explain heat stroke cases reported in low-risk populations performing routine activities. Importantly, we question the "traditional" notion that high core temperature is the critical mediator of exercise performance degradation and heat stroke. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.

  5. Osteopontin Expression in Acute Immune Response Mediates Hippocampal Synaptogenesis and Adaptive Outcome Following Cortical Brain Injury

    PubMed Central

    Chan, Julie L.; Reeves, Thomas M.; Phillips, Linda L.

    2014-01-01

    Traumatic brain injury (TBI) produces axotomy, deafferentation and reactive synaptogenesis. Inflammation influences synaptic repair, and the novel brain cytokine osteopontin (OPN) has potential to support axon regeneration through exposure of its integrin receptor binding sites. This study explored whether OPN secretion and proteolysis