Enhancement of infectious disease vaccines through TLR9-dependent recognition of CpG DNA.

PubMed

McCluskie, M J; Krieg, A M

2006-01-01

The adaptive immune system-with its remarkable ability to generate antigen-specific antibodies and T lymphocytes against pathogens never before "seen" by an organism-is one of the marvels of evolution. However, to generate these responses, the adaptive immune system requires activation by the innate immune system. Toll-like receptors (TLRs) are perhaps the best-understood family of innate immune receptors for detecting infections and stimulating adaptive immune responses. TLR9 appears to have evolved to recognize infections by a subtle structural difference between eukaryotic and prokaryotic/viral DNA; only the former frequently methylates CpG dinucleotides. Used as vaccine adjuvants, synthetic oligodeoxynucleotide (ODN) ligands for TLR9--CpG ODN--greatly enhance the speed and strength of the immune responses to vaccination.

'I know it has worked for millions of years': the role of the 'natural' in parental reasoning against child immunization in a qualitative study in Switzerland.

PubMed

Gross, Karin; Hartmann, Karin; Zemp, Elisabeth; Merten, Sonja

2015-04-12

Despite efforts of international and national health authorities, immunization coverage and timeliness of vaccination against dangerous childhood diseases have been adversely affected by parental hesitation to vaccinate their children in high-income countries. Literature shows that social and political processes and shifts in conceptual structures, such as emerging views linked to health and 'natural' lifestyles, have shaped parents' immunization decisions. This paper investigates how Swiss parents argued along the lines of a natural development of the child to explain their critical attitudes towards immunization against measles and other childhood diseases. A total of 32 semi-structured interviews were conducted with parents of children between 0 and 16 years of age who decided not to fully immunize their children. The interviews were analyzed using qualitative content analysis and an interpretative approach. Parents built their arguments against immunization on a strong faith in the strength of the naturally acquired immune system. Childhood diseases were not perceived as a threat but as part of the natural way to reinforce the body and to acquire a "natural" and thus strong immunity. Parents understood immunization as an artificial intrusion into the natural development of the immune system and feared overloading the still immature immune system of their young children and infants through current vaccination schemes. In the context of emerging trends towards natural lifestyles and ideas of holistic health in Switzerland and Europe, where many well-informed parents express concerns towards vaccinating their children, public vaccination strategies require reconsideration. Public immunization schedules need to acknowledge parents' wish for more flexibility and demand for an individualized patient-centered approach to immunization.

COMPUTATION OF ℛ IN AGE-STRUCTURED EPIDEMIOLOGICAL MODELS WITH MATERNAL AND TEMPORARY IMMUNITY.

PubMed

Feng, Zhilan; Han, Qing; Qiu, Zhipeng; Hill, Andrew N; Glasser, John W

2016-03-01

For infectious diseases such as pertussis, susceptibility is determined by immunity, which is chronological age-dependent. We consider an age-structured epidemiological model that accounts for both passively acquired maternal antibodies that decay and active immunity that wanes, permitting reinfection. The model is a 6-dimensional system of partial differential equations (PDE). By assuming constant rates within each age-group, the PDE system can be reduced to an ordinary differential equation (ODE) system with aging from one age-group to the next. We derive formulae for the effective reproduction number ℛ and provide their biological interpretation in some special cases. We show that the disease-free equilibrium is stable when ℛ < 1 and unstable if ℛ > 1.

[Relationships between venomous function and innate immune function].

PubMed

Goyffon, Max; Saul, Frederick; Faure, Grazyna

2015-01-01

Venomous function is investigated in relation to innate immune function in two cases selected from scorpion venom and serpent venom. In the first case, structural analysis of scorpion toxins and defensins reveals a close interrelation between both functions (toxic and innate immune system function). In the second case, structural and functional studies of natural inhibitors of toxic snake venom phospholipases A2 reveal homology with components of the innate immune system, leading to a similar conclusion. Although there is a clear functional distinction between neurotoxins, which act by targeting membrane ion channels, and the circulating defensins which protect the organism from pathogens, the scorpion short toxins and defensins share a common protein folding scaffold with a conserved cysteine-stabilized alpha-beta motif of three disulfide bridges linking a short alpha helix and an antiparallel beta sheet. Genomic analysis suggests that these proteins share a common ancestor (long venom toxins were separated from an early gene family which gave rise to separate short toxin and defensin families). Furthermore, a scorpion toxin has been experimentally synthetized from an insect defensin, and an antibacterial scorpion peptide, androctonin (whose structure is similar to that of a cone snail venom toxin), was shown to have a similar high affinity for the postsynaptic acetylcholine receptor of Torpedo sp. Natural inhibitors of phospholipase A2 found in the blood of snakes are associated with the resistance of venomous snakes to their own highly neurotoxic venom proteins. Three classes of phospholipases A2 inhibitors (PLI-α, PLI-β, PLI-γ) have been identified. These inhibitors display diverse structural motifs related to innate immune proteins including carbohydrate recognition domains (CRD), leucine rich repeat domains (found in Toll-like receptors) and three finger domains, which clearly differentiate them from components of the adaptive immune system. Thus, in structure, function and phylogeny, venomous function in both vertebrates and invertebrates are clearly interrelated with innate immune function. © Société de Biologie, 2016.

Assessment of geometry in 2D immune systems using high accuracy laser-based bioprinting techniques (Conference Presentation)

NASA Astrophysics Data System (ADS)

Lauzurica, Sara; Márquez, Andrés.; Molpeceres, Carlos; Notario, Laura; Gómez-Fontela, Miguel; Lauzurica, Pilar

2017-02-01

The immune system is a very complex system that comprises a network of genetic and signaling pathways subtending a network of interacting cells. The location of the cells in a network, along with the gene products they interact with, rules the behavior of the immune system. Therefore, there is a great interest in understanding properly the role of a cell in such networks to increase our knowledge of the immune system response. In order to acquire a better understanding of these processes, cell printing with high spatial resolution emerges as one of the promising approaches to organize cells in two and three-dimensional patterns to enable the study the geometry influence in these interactions. In particular, laser assisted bio-printing techniques using sub-nanosecond laser sources have better characteristics for application in this field, mainly due to its higher spatial resolution, cell viability percentage and process automation. This work presents laser assisted bio-printing of antigen-presenting cells (APCs) in two-dimensional geometries, placing cellular components on a matrix previously generated on demand, permitting to test the molecular interactions between APCs and lymphocytes; as well as the generation of two-dimensional structures designed ad hoc in order to study the mechanisms of mobilization of immune system cells. The use of laser assisted bio-printing, along with APCs and lymphocytes emulate the structure of different niches of the immune system so that we can analyse functional requirement of these interaction.

Exosomes and nanotubes: control of immune cell communication

PubMed Central

McCoy-Simandle, Kessler; Hanna, Samer J.; Cox, Dianne

2015-01-01

Cell-cell communication is critical to coordinate the activity and behavior of a multicellular organism. The cells of the immune system not only must communicate with similar cells, but also with many other cell types in the body. Therefore, the cells of the immune system have evolved multiple ways to communicate. Exosomes and tunneling nanotubes (TNTs) are two means of communication used by immune cells that contribute to immune functions. Exosomes are small membrane vesicles secreted by most cell types that can mediate intercellular communication and in the immune system they are proposed to play a role in antigen presentation and modulation of gene expression. TNTs are membranous structures that mediate direct cell-cell contact over several cell diameters in length (and possibly longer) and facilitate the interaction and/or the transfer of signals, material and other cellular organelles between connected cells. Recent studies have revealed additional, but sometimes conflicting, structural and functional features of both exosomes and TNTs. Despite the new and exciting information in exosome and TNT composition, origin and in vitro function, biologically significant functions are still being investigated and determined. In this review, we discuss the current field regarding exosomes and TNTs in immune cells providing evaluation and perspectives of the current literature. PMID:26704468

Clonal Selection Based Artificial Immune System for Generalized Pattern Recognition

NASA Technical Reports Server (NTRS)

Huntsberger, Terry

2011-01-01

The last two decades has seen a rapid increase in the application of AIS (Artificial Immune Systems) modeled after the human immune system to a wide range of areas including network intrusion detection, job shop scheduling, classification, pattern recognition, and robot control. JPL (Jet Propulsion Laboratory) has developed an integrated pattern recognition/classification system called AISLE (Artificial Immune System for Learning and Exploration) based on biologically inspired models of B-cell dynamics in the immune system. When used for unsupervised or supervised classification, the method scales linearly with the number of dimensions, has performance that is relatively independent of the total size of the dataset, and has been shown to perform as well as traditional clustering methods. When used for pattern recognition, the method efficiently isolates the appropriate matches in the data set. The paper presents the underlying structure of AISLE and the results from a number of experimental studies.

Genetic selection of cattle for improved immunity and health.

PubMed

Mallard, Bonnie A; Emam, Mehdi; Paibomesai, Marlene; Thompson-Crispi, Kathleen; Wagter-Lesperance, Lauraine

2015-02-01

The immune system is a sensing structure composed of tissues and molecules that are well integrated with the neuroendocrine system. This integrate system ensures non-self from self-discrimination. In this capacity the immune system provides detection and protection from a wide range of pathogens. In mammals, the immune system is regulated by several thousand genes (8-9% of the genome) which indicate its high genetic priority as a critical fitness trait providing survival of the species. Identifying and selectively breeding livestock with the inherent ability to make superior immune responses can reduce disease occurrence, improve milk quality and increase farm profitability. Healthier animals also may be expected to demonstrate improvements in other traits, including reproductive fitness. Using the University of Guelph's patented High Immune Response technology it is possible to classify animals as high, average, or low responders based on their genetic estimated breeding value for immune responsiveness. High responders have the inherent ability to produce more balanced and robust immune responses compared with average or low responders. High responders dairy cattle essentially have about one-half the disease occurrence of low responders, and can pass their superior immune response genes on to future generations thereby accumulating health benefits within the dairy herd.

Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF

PubMed Central

Felix, Jan; Kandiah, Eaazhisai; De Munck, Steven; Bloch, Yehudi; van Zundert, Gydo C.P.; Pauwels, Kris; Dansercoer, Ann; Novanska, Katka; Read, Randy J.; Bonvin, Alexandre M.J.J.; Vergauwen, Bjorn; Verstraete, Kenneth; Gutsche, Irina; Savvides, Savvas N.

2016-01-01

Subversion of the host immune system by viruses is often mediated by molecular decoys that sequester host proteins pivotal to mounting effective immune responses. The widespread mammalian pathogen parapox Orf virus deploys GIF, a member of the poxvirus immune evasion superfamily, to antagonize GM-CSF (granulocyte macrophage colony-stimulating factor) and IL-2 (interleukin-2), two pleiotropic cytokines of the mammalian immune system. However, structural and mechanistic insights into the unprecedented functional duality of GIF have remained elusive. Here we reveal that GIF employs a dimeric binding platform that sequesters two copies of its target cytokines with high affinity and slow dissociation kinetics to yield distinct complexes featuring mutually exclusive interaction footprints. We illustrate how GIF serves as a competitive decoy receptor by leveraging binding hotspots underlying the cognate receptor interactions of GM-CSF and IL-2, without sharing any structural similarity with the cytokine receptors. Our findings contribute to the tracing of novel molecular mimicry mechanisms employed by pathogenic viruses. PMID:27819269

Development of a human adaptive immune system in cord blood cell-transplanted mice.

PubMed

Traggiai, Elisabetta; Chicha, Laurie; Mazzucchelli, Luca; Bronz, Lucio; Piffaretti, Jean-Claude; Lanzavecchia, Antonio; Manz, Markus G

2004-04-02

Because ethical restrictions limit in vivo studies of the human hemato-lymphoid system, substitute human to small animal xenotransplantation models have been employed. Existing models, however, sustain only limited development and maintenance of human lymphoid cells and rarely produce immune responses. Here we show that intrahepatic injection of CD34+ human cord blood cells into conditioned newborn Rag2-/-gammac-/- mice leads to de novo development of B, T, and dendritic cells; formation of structured primary and secondary lymphoid organs; and production of functional immune responses. This provides a valuable model to study development and function of the human adaptive immune system in vivo.

Dynamic two-photon imaging of the immune response to Toxoplasma gondii infection.

PubMed

Luu, L; Coombes, J L

2015-03-01

Toxoplasma gondii is a highly successful parasite that can manipulate host immune responses to optimize its persistence and spread. As a result, a highly complex relationship exists between T. gondii and the immune system of the host. Advances in imaging techniques, and in particular, the application of two-photon microscopy to mouse infection models, have made it possible to directly visualize interactions between parasites and the host immune system as they occur in living tissues. Here, we will discuss how dynamic imaging techniques have provided unexpected new insight into (i) how immune responses are dynamically regulated by cells and structures in the local tissue environment, (ii) how protective responses to T. gondii are generated and (iii) how the parasite exploits the immune system for its own benefit. © 2014 John Wiley & Sons Ltd.

Ecosystem and immune systems: Hierarchial response provides resilience against invasions

USGS Publications Warehouse

Allen, Craig R.

2001-01-01

Janssen (2001) provides the stimulus for thoughtful comparison and consideration of the ranges of responses exhibited by immune systems and ecological systems in the face of perturbations such as biological invasions. It may indeed be informative to consider the similarities of the responses to invasions exhibited by immune systems and ecological systems. Clearly, both types of systems share a general organizational structure with all other complex hierarchical systems. Their organization provides these systems with resilience. However, when describing the response of ecological-economic systems to invasions, Janssen emphasizes the human-economic response. I would like to expand on his comparison by focusing on how resilience is maintained in complex systems under the threat of invasion.

The neuroendocrine immunomodulatory axis-like pathway mediated by circulating haemocytes in pacific oyster Crassostrea gigas.

PubMed

Liu, Zhaoqun; Zhou, Zhi; Jiang, Qiufen; Wang, Lingling; Yi, Qilin; Qiu, Limei; Song, Linsheng

2017-01-01

The neuroendocrine-immune (NEI) regulatory network is a complex system, which plays an indispensable role in the immunity of host. In this study, a neuroendocrine immunomodulatory axis (NIA)-like pathway mediated by the nervous system and haemocytes was characterized in the oyster Crassostrea gigas Once invaded pathogen was recognized by the host, the nervous system would temporally release neurotransmitters to modulate the immune response. Instead of acting passively, oyster haemocytes were able to mediate neuronal immunomodulation promptly by controlling the expression of specific neurotransmitter receptors on cell surface and modulating their binding sensitivities, thus regulating intracellular concentration of Ca 2+ This neural immunomodulation mediated by the nervous system and haemocytes could influence cellular immunity in oyster by affecting mRNA expression level of TNF genes, and humoral immunity by affecting the activities of key immune-related enzymes. In summary, though simple in structure, the 'nervous-haemocyte' NIA-like pathway regulates both cellular and humoral immunity in oyster, meaning a world to the effective immune regulation of the NEI network. © 2017 The Authors.

[The immune system and the eye].

PubMed

Faber, Carsten; Nissen, Mogens Holst

2008-09-15

The special relationship between the eye and the immune system rests on a number of anatomical, physiological and immunological mechanisms. These mechanisms prevent the delicate structures of the eye from potentially damaging immunogenic inflammation while protecting against pathogens. Rather than inflammation, antigen induces a form of systemic and antigen-specific immunological tolerance. Owing to its systemic nature, this tolerance may be utilised to achieve successful treatment of immunological disorders.

Biomimetic structural engineering of P22 virus-like particles for catalysis and immune modulation

NASA Astrophysics Data System (ADS)

Schwarz, Benjamin

Within biology molecules are arranged in hierarchical structures that coordinate and control the many processes that allow for complex organisms to exist. Proteins and other functional macromolecules are often studied outside their natural nanostructural context because it remains difficult to create controlled arrangements of proteins at this size scale. Viruses are elegantly simple nano-systems that exist at the interface of living organisms and non-living biological machines. Studied and viewed primarily as pathogens to be combatted, viruses have emerged as models of structural efficiency at the nanoscale and have spurred the development of biomimetic nanoparticle systems. Virus-like particles (VLPs) are noninfectious protein cages derived from viruses or other cage-forming systems. VLPs provide incredibly regular scaffolds for building at the nanoscale. In this work I have utilized the VLP derived from the bacteriophage P22 as a platform for the organization of enzymes, antigens, and immune-stimulating proteins inside and outside the capsid through purely genetic means. In the case of enzymes, encapsulation of a two-enzyme pathway has led to the development of metabolic nanoparticle catalysts and an expanded understanding of the control that structure exerts on metabolic flux. These same structural elements applied to the delivery of protein subunit antigens directed at cytotoxic T cell immunity result in drastically enhanced antigen processing and lasting immunological memory. Lastly, presentation of immune-stimulating proteins from the Tumor Necrosis Factor Super Family on the surface of the P22 VLP enhances the cell signaling efficiency of these compounds 50-fold and provides strategies for the application of these proteins as immune modulatory oncology therapeutics. In all of these cases, the reintroduction of nanostructure to these protein systems, reminiscent of their natural environment, has led to both new technologies and a better understanding of the role of structure in biological processes.

Complement factor H in host defense and immune evasion.

PubMed

Parente, Raffaella; Clark, Simon J; Inforzato, Antonio; Day, Anthony J

2017-05-01

Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer.

A SOA-Based Solution to Monitor Vaccination Coverage Among HIV-Infected Patients in Liguria.

PubMed

Giannini, Barbara; Gazzarata, Roberta; Sticchi, Laura; Giacomini, Mauro

2016-01-01

Vaccination in HIV-infected patients constitutes an essential tool in the prevention of the most common infectious diseases. The Ligurian Vaccination in HIV Program is a proposed vaccination schedule specifically dedicated to this risk group. Selective strategies are proposed within this program, employing ICT (Information and Communication) tools to identify this susceptible target group, to monitor immunization coverage over time and to manage failures and defaulting. The proposal is to connect an immunization registry system to an existing regional platform that allows clinical data re-use among several medical structures, to completely manage the vaccination process. This architecture will adopt a Service Oriented Architecture (SOA) approach and standard HSSP (Health Services Specification Program) interfaces to support interoperability. According to the presented solution, vaccination administration information retrieved from the immunization registry will be structured according to the specifications within the immunization section of the HL7 (Health Level 7) CCD (Continuity of Care Document) document. Immunization coverage will be evaluated through the continuous monitoring of serology and antibody titers gathered from the hospital LIS (Laboratory Information System) structured into a HL7 Version 3 (v3) Clinical Document Architecture Release 2 (CDA R2).

[Environmental pollutants as adjuvant factors of immune system derived diseases].

PubMed

Lehmann, Irina

2017-06-01

The main task of the immune system is to protect the body against invading pathogens. To be able to do so, immune cells must be able to recognize and combat exogenous challenges and at the same time tolerate body-borne structures. A complex regulatory network controls the sensitive balance between defense and tolerance. Perturbation of this network ultimately leads to the development of chronic inflammation, such as allergies, autoimmune reactions, and infections, because the immune system is no longer able to efficiently eliminate invading pathogens. Environmental pollutants can cause such perturbations by affecting the function of immune cells in such a way that they would react hypersensitively against allergens and the body's own structures, respectively, or that they would be no longer able to adequately combat pathogens. This indirect effect is also known as adjuvant effect. For pesticides, heavy metals, wood preservatives, or volatile organic compounds such adjuvant effects are well known. Examples of the mechanism by which environmental toxins contribute to chronic inflammatory diseases are manifold and will be discussed along asthma and allergies.While the immune system of healthy adults is typically well able to distinguish between foreign and endogenous substances even under adverse environmental conditions, that of children would react much more sensible upon comparable environmental challenges. To prevent priming for diseases by environmental cues during that highly sensitive period of early childhood children are to be particularly protected.

Structural and functional features of central nervous system lymphatics

PubMed Central

Louveau, Antoine; Smirnov, Igor; Keyes, Timothy J.; Eccles, Jacob D.; Rouhani, Sherin J.; Peske, J. David; Derecki, Noel C.; Castle, David; Mandell, James W.; Kevin, S. Lee; Harris, Tajie H.; Kipnis, Jonathan

2015-01-01

One of the characteristics of the CNS is the lack of a classical lymphatic drainage system. Although it is now accepted that the CNS undergoes constant immune surveillance that takes place within the meningeal compartment1–3, the mechanisms governing the entrance and exit of immune cells from the CNS remain poorly understood4–6. In searching for T cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the CSF, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the CNS. The discovery of the CNS lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction. PMID:26030524

DOE Office of Scientific and Technical Information (OSTI.GOV)

Srikannathasan, Velupillai; English, Grant; Bui, Nhat Khai

Crystal structures of type VI secretion system-associated immunity proteins, a peptidoglycan endopeptidase and a complex of the endopeptidase and its cognate immunity protein are reported together with assays of endopeptidase activity and functional assessment. Some Gram-negative bacteria target their competitors by exploiting the type VI secretion system to extrude toxic effector proteins. To prevent self-harm, these bacteria also produce highly specific immunity proteins that neutralize these antagonistic effectors. Here, the peptidoglycan endopeptidase specificity of two type VI secretion-system-associated effectors from Serratia marcescens is characterized. These small secreted proteins, Ssp1 and Ssp2, cleave between γ-d-glutamic acid and l-meso-diaminopimelic acid with differentmore » specificities. Ssp2 degrades the acceptor part of cross-linked tetratetrapeptides. Ssp1 displays greater promiscuity and cleaves monomeric tripeptides, tetrapeptides and pentapeptides and dimeric tetratetra and tetrapenta muropeptides on both the acceptor and donor strands. Functional assays confirm the identity of a catalytic cysteine in these endopeptidases and crystal structures provide information on the structure–activity relationships of Ssp1 and, by comparison, of related effectors. Functional assays also reveal that neutralization of these effectors by their cognate immunity proteins, which are called resistance-associated proteins (Raps), contributes an essential role to cell fitness. The structures of two immunity proteins, Rap1a and Rap2a, responsible for the neutralization of Ssp1 and Ssp2-like endopeptidases, respectively, revealed two distinct folds, with that of Rap1a not having previously been observed. The structure of the Ssp1–Rap1a complex revealed a tightly bound heteromeric assembly with two effector molecules flanking a Rap1a dimer. A highly effective steric block of the Ssp1 active site forms the basis of effector neutralization. Comparisons with Ssp2–Rap2a orthologues suggest that the specificity of these immunity proteins for neutralizing effectors is fold-dependent and that in cases where the fold is conserved sequence differences contribute to the specificity of effector–immunity protein interactions.« less

Effects of short-term hypothermal and contrast exposure on immunophysiological parameters of laboratory animals.

PubMed

Kalenova, L F; Fisher, T A; Suhovey, J G; Besedin, I M

2009-05-01

Experiments on inbred animals showed that short-term exposure in cold water significantly modified structural and functional parameters of the immune system at different levels of its organization, from bone marrow hemopoiesis to effector stage of the immune response to antigen. The thermal factor caused changes in nonspecific and specific mechanisms of the immune system. Hypothermal exposure (7-9 degrees C, 5 sec) increased the thymic index and bone marrow lymphocyte count, reduced absorption capacity and stimulated metabolic activity of phagocytes, stimulated cell-mediated and suppressed humoral immunity. Contrast exposure in cold and hot water (7-9 degrees C, 5 sec/40-42 degrees C, 30 sec) increased monocyte count in bone marrow and reduced it in the their peripheral blood, reduced metabolic activity of phagocytes, stimulated cell-mediated and suppressed humoral immunity. These data demonstrate physiological mechanisms of interactions between the thermoregulatory and immune systems.

[Plant immune system: the basal immunity].

PubMed

Shamraĭ, S N

2014-01-01

Plants have an efficient system of innate immunity which is based on the effective detection of potentially harmful microorganisms and rapid induction of defense responses. The first level of plant immunity is the basal immunity which is induced by the conserved molecular structures of microbes such as bacterial flagellins or fungal chitin, or molecules that result from the interaction of plants with pathogens, for example oligosaccharides and peptides ("danger signals"). Plants recognize these inducers through receptors localized to the plasma membrane, represented mainly receptor-like protein kinases or receptor-like proteins. Activation of the receptor by a ligand triggers a complex network of signaling events which eventually cause an array of plant defense responses to prevent further spread of the pathogen.

Viral Replication Complexes Are Targeted by LC3-Guided Interferon-Inducible GTPases.

PubMed

Biering, Scott B; Choi, Jayoung; Halstrom, Rachel A; Brown, Hailey M; Beatty, Wandy L; Lee, Sanghyun; McCune, Broc T; Dominici, Erin; Williams, Lelia E; Orchard, Robert C; Wilen, Craig B; Yamamoto, Masahiro; Coers, Jörn; Taylor, Gregory A; Hwang, Seungmin

2017-07-12

All viruses with positive-sense RNA genomes replicate on membranous structures in the cytoplasm called replication complexes (RCs). RCs provide an advantageous microenvironment for viral replication, but it is unknown how the host immune system counteracts these structures. Here we show that interferon-gamma (IFNG) disrupts the RC of murine norovirus (MNV) via evolutionarily conserved autophagy proteins and the induction of IFN-inducible GTPases, which are known to destroy the membrane of vacuoles containing bacteria, protists, or fungi. The MNV RC was marked by the microtubule-associated-protein-1-light-chain-3 (LC3) conjugation system of autophagy and then targeted by immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs) upon their induction by IFNG. Further, the LC3 conjugation system and the IFN-inducible GTPases were necessary to inhibit MNV replication in mice and human cells. These data suggest that viral RCs can be marked and antagonized by a universal immune defense mechanism targeting diverse pathogens replicating in cytosolic membrane structures. Copyright © 2017 Elsevier Inc. All rights reserved.

Mining the human gut microbiota for effector strains that shape the immune system

PubMed Central

Ahern, Philip P.; Faith, Jeremiah J.; Gordon, Jeffrey I.

2014-01-01

Summary The gut microbiota co-develops with the immune system beginning at birth. Mining the microbiota for bacterial strains responsible for shaping the structure and dynamic operations of the innate and adaptive arms of the immune system represents a formidable combinatorial problem but one that needs to be overcome to advance mechanistic understanding of microbial community-immune system co-regulation, and in order to develop new diagnostic and therapeutic approaches that promote health. Here, we discuss a scalable, less biased approach for identifying effector strains in complex microbial communities that impact immune function. The approach begins by identifying uncultured human fecal microbiota samples that transmit immune phenotypes to germ-free mice. Clonally-arrayed sequenced collections of bacterial strains are constructed from representative donor microbiota. If the collection transmits phenotypes, effector strains are identified by testing randomly generated subsets with overlapping membership in individually-housed germ-free animals. Detailed mechanistic studies of effector strain-host interactions can then be performed. PMID:24950201

Novel structural features in Candida albicans hyphal glucan provide a basis for differential innate immune recognition of hyphae versus yeast.

PubMed

Lowman, Douglas W; Greene, Rachel R; Bearden, Daniel W; Kruppa, Michael D; Pottier, Max; Monteiro, Mario A; Soldatov, Dmitriy V; Ensley, Harry E; Cheng, Shih-Chin; Netea, Mihai G; Williams, David L

2014-02-07

The innate immune system differentially recognizes Candida albicans yeast and hyphae. It is not clear how the innate immune system effectively discriminates between yeast and hyphal forms of C. albicans. Glucans are major components of the fungal cell wall and key fungal pathogen-associated molecular patterns. C. albicans yeast glucan has been characterized; however, little is known about glucan structure in C. albicans hyphae. Using an extraction procedure that minimizes degradation of the native structure, we extracted glucans from C. albicans hyphal cell walls. (1)H NMR data analysis revealed that, when compared with reference (1→3,1→6) β-linked glucans and C. albicans yeast glucan, hyphal glucan has a unique cyclical or "closed chain" structure that is not found in yeast glucan. GC/MS analyses showed a high abundance of 3- and 6-linked glucose units when compared with yeast β-glucan. In addition to the expected (1→3), (1→6), and 3,6 linkages, we also identified a 2,3 linkage that has not been reported previously in C. albicans. Hyphal glucan induced robust immune responses in human peripheral blood mononuclear cells and macrophages via a Dectin-1-dependent mechanism. In contrast, C. albicans yeast glucan was a much less potent stimulus. We also demonstrated the capacity of C. albicans hyphal glucan, but not yeast glucan, to induce IL-1β processing and secretion. This finding provides important evidence for understanding the immune discrimination between colonization and invasion at the mucosal level. When taken together, these data provide a structural basis for differential innate immune recognition of C. albicans yeast versus hyphae.

Novel Structural Features in Candida albicans Hyphal Glucan Provide a Basis for Differential Innate Immune Recognition of Hyphae Versus Yeast*

PubMed Central

Lowman, Douglas W.; Greene, Rachel R.; Bearden, Daniel W.; Kruppa, Michael D.; Pottier, Max; Monteiro, Mario A.; Soldatov, Dmitriy V.; Ensley, Harry E.; Cheng, Shih-Chin; Netea, Mihai G.; Williams, David L.

2014-01-01

The innate immune system differentially recognizes Candida albicans yeast and hyphae. It is not clear how the innate immune system effectively discriminates between yeast and hyphal forms of C. albicans. Glucans are major components of the fungal cell wall and key fungal pathogen-associated molecular patterns. C. albicans yeast glucan has been characterized; however, little is known about glucan structure in C. albicans hyphae. Using an extraction procedure that minimizes degradation of the native structure, we extracted glucans from C. albicans hyphal cell walls. 1H NMR data analysis revealed that, when compared with reference (1→3,1→6) β-linked glucans and C. albicans yeast glucan, hyphal glucan has a unique cyclical or “closed chain” structure that is not found in yeast glucan. GC/MS analyses showed a high abundance of 3- and 6-linked glucose units when compared with yeast β-glucan. In addition to the expected (1→3), (1→6), and 3,6 linkages, we also identified a 2,3 linkage that has not been reported previously in C. albicans. Hyphal glucan induced robust immune responses in human peripheral blood mononuclear cells and macrophages via a Dectin-1-dependent mechanism. In contrast, C. albicans yeast glucan was a much less potent stimulus. We also demonstrated the capacity of C. albicans hyphal glucan, but not yeast glucan, to induce IL-1β processing and secretion. This finding provides important evidence for understanding the immune discrimination between colonization and invasion at the mucosal level. When taken together, these data provide a structural basis for differential innate immune recognition of C. albicans yeast versus hyphae. PMID:24344127

Structure-informed insights for NLR functioning in plant immunity.

PubMed

Sukarta, Octavina C A; Slootweg, Erik J; Goverse, Aska

2016-08-01

To respond to foreign invaders, plants have evolved a cell autonomous multilayered immune system consisting of extra- and intracellular immune receptors. Nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) mediate recognition of pathogen effectors inside the cell and trigger a host specific defense response, often involving controlled cell death. NLRs consist of a central nucleotide-binding domain, which is flanked by an N-terminal CC or TIR domain and a C-terminal leucine-rich repeat domain (LRR). These multidomain proteins function as a molecular switch and their activity is tightly controlled by intra and inter-molecular interactions. In contrast to metazoan NLRs, the structural basis underlying NLR functioning as a pathogen sensor and activator of immune responses in plants is largely unknown. However, the first crystal structures of a number of plant NLR domains were recently obtained. In addition, biochemical and structure-informed analyses revealed novel insights in the cooperation between NLR domains and the formation of pre- and post activation complexes, including the coordinated activity of NLR pairs as pathogen sensor and executor of immune responses. Moreover, the discovery of novel integrated domains underscores the structural diversity of NLRs and provides alternative models for how these immune receptors function in plants. In this review, we will highlight these recent advances to provide novel insights in the structural, biochemical and molecular aspects involved in plant NLR functioning. Copyright © 2016 Elsevier Ltd. All rights reserved.

Immune regulation of systemic hypertension, pulmonary arterial hypertension, and preeclampsia: shared disease mechanisms and translational opportunities.

PubMed

Jafri, Salema; Ormiston, Mark L

2017-12-01

Systemic hypertension, preeclampsia, and pulmonary arterial hypertension (PAH) are diseases of high blood pressure in the systemic or pulmonary circulation. Beyond the well-defined contribution of more traditional pathophysiological mechanisms, such as changes in the renin-angiotensin-aldosterone system, to the development of these hypertensive disorders, there is substantial clinical evidence supporting an important role for inflammation and immunity in the pathogenesis of each of these three conditions. Over the last decade, work in small animal models, bearing targeted deficiencies in specific cytokines or immune cell subsets, has begun to clarify the immune-mediated mechanisms that drive changes in vascular structure and tone in hypertensive disease. By summarizing the clinical and experimental evidence supporting a contribution of the immune system to systemic hypertension, preeclampsia, and PAH, the current review highlights the cellular and molecular pathways that are common to all three hypertensive disorders. These mechanisms are centered on an imbalance in CD4 + helper T cell populations, defined by excessive Th17 responses and impaired T reg activity, as well as the excessive activation or impairment of additional immune cell types, including macrophages, dendritic cells, CD8 + T cells, B cells, and natural killer cells. The identification of common immune mechanisms in systemic hypertension, preeclampsia, and PAH raises the possibility of new therapeutic strategies that target the immune component of hypertension across multiple disorders. Copyright © 2017 the American Physiological Society.

The development of a fully-integrated immune response model (FIRM) simulator of the immune response through integration of multiple subset models

PubMed Central

2013-01-01

Background The complexity and multiscale nature of the mammalian immune response provides an excellent test bed for the potential of mathematical modeling and simulation to facilitate mechanistic understanding. Historically, mathematical models of the immune response focused on subsets of the immune system and/or specific aspects of the response. Mathematical models have been developed for the humoral side of the immune response, or for the cellular side, or for cytokine kinetics, but rarely have they been proposed to encompass the overall system complexity. We propose here a framework for integration of subset models, based on a system biology approach. Results A dynamic simulator, the Fully-integrated Immune Response Model (FIRM), was built in a stepwise fashion by integrating published subset models and adding novel features. The approach used to build the model includes the formulation of the network of interacting species and the subsequent introduction of rate laws to describe each biological process. The resulting model represents a multi-organ structure, comprised of the target organ where the immune response takes place, circulating blood, lymphoid T, and lymphoid B tissue. The cell types accounted for include macrophages, a few T-cell lineages (cytotoxic, regulatory, helper 1, and helper 2), and B-cell activation to plasma cells. Four different cytokines were accounted for: IFN-γ, IL-4, IL-10 and IL-12. In addition, generic inflammatory signals are used to represent the kinetics of IL-1, IL-2, and TGF-β. Cell recruitment, differentiation, replication, apoptosis and migration are described as appropriate for the different cell types. The model is a hybrid structure containing information from several mammalian species. The structure of the network was built to be physiologically and biochemically consistent. Rate laws for all the cellular fate processes, growth factor production rates and half-lives, together with antibody production rates and half-lives, are provided. The results demonstrate how this framework can be used to integrate mathematical models of the immune response from several published sources and describe qualitative predictions of global immune system response arising from the integrated, hybrid model. In addition, we show how the model can be expanded to include novel biological findings. Case studies were carried out to simulate TB infection, tumor rejection, response to a blood borne pathogen and the consequences of accounting for regulatory T-cells. Conclusions The final result of this work is a postulated and increasingly comprehensive representation of the mammalian immune system, based on physiological knowledge and susceptible to further experimental testing and validation. We believe that the integrated nature of FIRM has the potential to simulate a range of responses under a variety of conditions, from modeling of immune responses after tuberculosis (TB) infection to tumor formation in tissues. FIRM also has the flexibility to be expanded to include both complex and novel immunological response features as our knowledge of the immune system advances. PMID:24074340

Steroids and Autoimmunity.

PubMed

Trombetta, Amelia Chiara; Meroni, Marianna; Cutolo, Maurizio

2017-01-01

From the middle of the 19th century, it is known that endocrine and immune systems interact bi-directionally in different processes that ensure organism homeostasis. Endocrine and nervous systems have a pivotal role in the balancing of pro- and anti-inflammatory functions of immune system, and constitute a complex circadian neuroendocrine network. Autoimmune diseases have in fact a complex pathogenic origin in which the importance of endocrine system was demonstrated. In this chapter, we will mention the structure and function of steroidal hormones involved in the neuroendocrine immune network and we will address the ways in which endocrine and immune systems influence each other, in a bi-directional fashion. Adrenal hormones, sex hormones, vitamin D, and melatonin and prolactin importantly all contribute to the homeostasis of the immune system. Indeed, some of the steroidal hormone activities determine inhibition or stimulation of immune system components, in both physiological (i.e. suppression of an unwanted response in pregnancy, or stimulation of a protective response in infections) and pathological conditions. We will finally mention the rationale for optimization of exogenous administration of glucocorticoids in chronic autoimmune diseases, and the latest developments concerning these drugs. © 2017 S. Karger AG, Basel.

Immune Organs and Haemopoietic System Under Modelling of the Mission Factors

NASA Astrophysics Data System (ADS)

Sapin, M. R.; Grigoriev, A. I.; Erofeeva, L. M.; Grigorenko, D. E.; Fedorenko, B. S.

1997-07-01

Literary and experimental data on the character of changes in immune organs and lymphoid tissue of respiratory system and digestive system in laboratory animals during the mission factors model are given. Inhibition of reproductive function in bone marrow, thymus and spleen under irradiation of gamma-rays and accelerated carbon ions, tensity of immune response in the lymphoid structures of larynx, trachea and bronchi under the influence of acetaldehyde vapors and decrease of lymphoid tissue square on histological series in spleen and small intestine with an increase of concentration of microbial bodies in the drinking water were estimated.

A perspective of nanotechnology in hypersensitivity reactions including drug allergy.

PubMed

Montañez, Maria Isabel; Ruiz-Sanchez, Antonio J; Perez-Inestrosa, Ezequiel

2010-08-01

We provide an overview of the application of the concepts of nanoscience and nanotechnology as a novel scientific approach to the area of nanomedicine related to the domain of the immune system. Particular emphasis will be paid to studies on drug allergy reactions. Several well defined chemical structures arranged in the dimension of the nanoscale are currently being studied for biomedical purposes. By interacting with the immune system, some of these show promising applications as vaccines, diagnostic tools and activators/effectors of the immune response. Even a brief listing of some key applications of nanostructured materials shows how broad and intense this area of nanomedicine is. As a result of the development of nanoscience and nanotechnology applied to medicine, new approaches can be envisioned for problems related to the modulation of the immune response, as well as in immunodiagnosis, and to design new tools to solve related medical challenges. Nanoparticles offer unique advantages with which to exploit new properties and for materials to play a major role in new diagnostic techniques and therapies. Fullerene-C60 and multivalent functionalized gold nanoparticles of various sizes have led to new tools and opened up new ways to study and interact with the immune system. Some of the most versatile nanostructures are dendrimers. In their interaction with the immune system they can naturally occurring macromolecules, taking advantage of the fact that dendrimers can be synthesized into nanosized structures. Their multivalence can be successfully exploited in vaccines and diagnostic tests for allergic reactions.

DNA extracellular traps are part of the immune repertoire of Periplaneta americana.

PubMed

Nascimento, M T C; Silva, K P; Garcia, M C F; Medeiros, M N; Machado, E A; Nascimento, S B; Saraiva, E M

2018-07-01

Extracellular traps (ETs), web-like structures composed of DNA and histones, are released by innate immune cells in a wide range of organisms. ETs capture microorganisms, thereby avoiding their spread, and also concentrate antimicrobial molecules, which helps to kill microbes. Although vertebrate innate immune systems share homology with the insect immune system, ETosis have yet to be characterized in insects. Here, we report that the hemocytes of the hemimetabolous insect Periplaneta americana release ETs upon in vitro stimulation. We further discuss the relationship between ETs and nodulation and in controlling bacterial spread in vivo. Copyright © 2018 Elsevier Ltd. All rights reserved.

Crystal Structure of Streptococcus pyogenes Cas1 and Its Interaction with Csn2 in the Type II CRISPR-Cas System.

PubMed

Ka, Donghyun; Lee, Hasup; Jung, Yi-Deun; Kim, Kyunggon; Seok, Chaok; Suh, Nayoung; Bae, Euiyoung

2016-01-05

CRISPRs and Cas proteins constitute an RNA-guided microbial immune system against invading nucleic acids. Cas1 is a universal Cas protein found in all three types of CRISPR-Cas systems, and its role is implicated in new spacer acquisition during CRISPR-mediated adaptive immunity. Here, we report the crystal structure of Streptococcus pyogenes Cas1 (SpCas1) in a type II CRISPR-Cas system and characterize its interaction with S. pyogenes Csn2 (SpCsn2). The SpCas1 structure reveals a unique conformational state distinct from type I Cas1 structures, resulting in a more extensive dimerization interface, a more globular overall structure, and a disruption of potential metal-binding sites for catalysis. We demonstrate that SpCas1 directly interacts with SpCsn2, and identify the binding interface and key residues for Cas complex formation. These results provide structural information for a type II Cas1 protein, and lay a foundation for studying multiprotein Cas complexes functioning in type II CRISPR-Cas systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

Immunization strategy for epidemic spreading on multilayer networks

NASA Astrophysics Data System (ADS)

Buono, C.; Braunstein, L. A.

2015-01-01

In many real-world complex systems, individuals have many kinds of interactions among them, suggesting that it is necessary to consider a layered-structure framework to model systems such as social interactions. This structure can be captured by multilayer networks and can have major effects on the spreading of process that occurs over them, such as epidemics. In this letter we study a targeted immunization strategy for epidemic spreading over a multilayer network. We apply the strategy in one of the layers and study its effect in all layers of the network disregarding degree-degree correlation among layers. We found that the targeted strategy is not as efficient as in isolated networks, due to the fact that in order to stop the spreading of the disease it is necessary to immunize more than 80% of the individuals. However, the size of the epidemic is drastically reduced in the layer where the immunization strategy is applied compared to the case with no mitigation strategy. Thus, the immunization strategy has a major effect on the layer were it is applied, but does not efficiently protect the individuals of other layers.

Primer on the Immune System.

PubMed

Spiering, Martin J

2015-01-01

The human body regularly encounters and combats many pathogenic organisms and toxic molecules. Its ensuing responses to these disease-causing agents involve two interrelated systems: innate immunity and adaptive (or acquired) immunity. Innate immunity is active at several levels, both at potential points of entry and inside the body (see figure). For example, the skin represents a physical barrier preventing pathogens from invading internal tissues. Digestive enzymes destroy microbes that enter the stomach with food. Macrophages and lymphocytes, equipped with molecular detectors, such as Toll-like receptors (TLRs), which latch onto foreign structures and activate cellular defenses, patrol the inside of the body. These immune cells sense and devour microbes, damaged cells, and other foreign materials in the body. Certain proteins in the blood (such as proteins of the complement system and those released by natural killer cells, along with antimicrobial host-defense peptides) attach to foreign organisms and toxins to initiate their destruction.

Understanding Internal Accountability in Nigeria’s Routine Immunization System: Perspectives From Government Officials at the National, State, and Local Levels

PubMed Central

Erchick, Daniel J.; George, Asha S.; Umeh, Chukwunonso; Wonodi, Chizoba

2017-01-01

Background: Routine immunization coverage in Nigeria has remained low, and studies have identified a lack of accountability as a barrier to high performance in the immunization system. Accountability lies at the heart of various health systems strengthening efforts recently launched in Nigeria, including those related to immunization. Our aim was to understand the views of health officials on the accountability challenges hindering immunization service delivery at various levels of government. Methods: A semi-structured questionnaire was used to interview immunization and primary healthcare (PHC) officials from national, state, local, and health facility levels in Niger State in north central Nigeria. Individuals were selected to represent a range of roles and responsibilities in the immunization system. The questionnaire explored concepts related to internal accountability using a framework that organizes accountability into three axes based upon how they drive change in the health system. Results: Respondents highlighted accountability challenges across multiple components of the immunization system, including vaccine availability, financing, logistics, human resources, and data management. A major focus was the lack of clear roles and responsibilities both within institutions and between levels of government. Delays in funding, especially at lower levels of government, disrupted service delivery. Supervision occurred less frequently than necessary, and the limited decision space of managers prevented problems from being resolved. Motivation was affected by the inability of officials to fulfill their responsibilities. Officials posited numerous suggestions to improve accountability, including clarifying roles and responsibilities, ensuring timely release of funding, and formalizing processes for supervision, problem solving, and data reporting. Conclusion: Weak accountability presents a significant barrier to performance of the routine immunization system and high immunization coverage in Nigeria. As one stakeholder in ensuring the performance of health systems, routine immunization officials reveal critical areas that need to be prioritized if emerging interventions to improve accountability in routine immunization are to have an effect. PMID:28812836

Porcine reproductive and respiratory syndrome virus (PRRSV): pathogenesis and interaction with the immune System

USDA-ARS?s Scientific Manuscript database

This review addresses important issues of porcine reproductive and respiratory syndrome virus (PRRSV) infection, immunity, pathogenesis and control. Worldwide PRRS is the most economically important infectious disease of pigs. We highlight the latest information on viral genome structure, pathogenic...

Engineering intranasal mRNA vaccines to enhance lymph node trafficking and immune responses.

PubMed

Li, Man; Li, You; Peng, Ke; Wang, Ying; Gong, Tao; Zhang, Zhirong; He, Qin; Sun, Xun

2017-12-01

Intranasal mRNA vaccination provides immediate immune protection against pandemic diseases. Recent studies have shown that diverse forms of polyethyleneimine (PEI) have potent mucosal adjuvant activity, which could significantly facilitate the delivery of intranasal mRNA vaccines. Nevertheless, optimizing the chemical structure of PEI to maximize its adjuvanticity and decrease its toxicity remains a challenge. Here we show that the chemical structure of PEI strongly influences how well nanocomplexes of PEI and mRNA migrate to the lymph nodes and elicit immune responses. Conjugating cyclodextrin (CD) with PEI600 or PEI2k yielded CP (CD-PEI) polymers with different CD/PEI ratios. We analyzed the delivery efficacy of CP600, CP2k, and PEI25k as intranasal mRNA vaccine carriers by evaluating the lymph nodes migration and immune responses. Among these polymers, CP2k/mRNA showed significantly higher in vitro transfection efficiency, stronger abilities to migrate to lymph nodes and stimulate dendritic cells maturation in vivo, which further led to potent humoral and cellular immune responses, and showed lower local and systemic toxicity than PEI25k/mRNA. These results demonstrate the potential of CD-PEI2k/mRNA nanocomplex as a self-adjuvanting vaccine delivery vehicle that traffics to lymph nodes with high efficiency. As we face outbreaks of pandemic diseases such as Zika virus, intranasal mRNA vaccination provides instant massive protection against highly variant viruses. Various polymer-based delivery systems have been successfully applied in intranasal vaccine delivery. However, the influence of molecular structure of the polymeric carriers on the lymph node trafficking and dendritic cell maturation is seldom studied for intranasal vaccination. Therefore, engineering polymer-based vaccine delivery system and elucidating the relationship between molecular structure and the intranasal delivery efficiency are essential for maximizing the immune responses. We hereby construct self-adjuvanting polymer-based intranasal mRNA vaccines to enhance lymph node trafficking and further improve immune responses. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Morphostructure of Immune System Organs in Cattle of Different Age.

PubMed

Gasisova, A I; Atkenova, A B; Ahmetzhanova, N B; Murzabekova, L M; Bekenova, A C

2017-04-01

This article provides comprehensive consideration of the age-dependent morphofunctional state of organs and tissues of the immune system (thymus, spleen, superficial and deep lymph nodes) in cattle. The morphofunctional maturity of organs and tissues of the immune system in cattle will be taken into account in various experimental studies, preventive and therapeutic measures. Performed analysis provides description of the spleen formation as well as the thymus and lymph nodes in post-natal ontogenesis and the macro- and microscopic structure of lymphoid cells and macrophages. The obtained results can be used to study immune responses of the thymus, spleen, lymph nodes in the pathological immunogenesis and may serve as a basis for development of recommendations related to diagnosis and treatment of diseases of the cattle immune system. The morphofunctional state of organs and tissues of the immune system in cattle was first studied with regard to the age dynamics. Based on the immunohistological studies, this article described the distribution and topography of immunocompetent cells (T lymphocytes, B lymphocytes and macrophages) and proliferative activity of lymphoid cells in the lymphoid organs and tissues in cattle. © 2016 Blackwell Verlag GmbH.

Breaking ignorance: the case of the brain.

PubMed

Wekerle, H

2006-01-01

Immunological self-tolerance is maintained through diverse mechanisms, including deletion of autoreactive immune cells following confrontation with autoantigen in the thymus or in the periphery and active suppression by regulatory cells. A third way to prevent autoimmunity is by hiding self tissues behind a tissue barrier impermeable for circulating immune cells. The latter mechanism has been held responsible for self-tolerance within the nervous tissue. Indeed, the nervous tissues enjoy a conditionally privileged immune status: they are normally unreachable for self-reactive T and B cells, they lack lymphatic drainage, and they are deficient in local antigen-presenting cells. Yet the immune system is by no means fully ignorant of the nervous structures. An ever-growing number of brain specific autoantigens is expressed within the thymus, which ensures an early confrontation with the unfolding T cell repertoire, and there is evidence that B cells also contact CNS-like structures outside of the brain. Then pathological processes such as neurodegeneration commonly lift the brain's immune privilege, shifting the local milieus from immune-hostile to immune-friendly. Finally, brain-reactive T cells, which abound in the healthy immune repertoire, but remain innocuous throughout life, can be activated and gain access to their target tissues. On their way, they take an ordered migration through peripheral lymphoid tissues and blood circulation, and undergo a profound reprogramming of their gene expression profile, which renders them fit to enter the nervous system and to interact with local cellule elements.

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

PubMed Central

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

2013-01-01

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. PMID:24427535

Using Human Factors Techniques to Design Text Message Reminders for Childhood Immunization

ERIC Educational Resources Information Center

Ahlers-Schmidt, Carolyn R.; Hart, Traci; Chesser, Amy; Williams, Katherine S.; Yaghmai, Beryl; Shah-Haque, Sapna; Wittler, Robert R.

2012-01-01

This study engaged parents to develop concise, informative, and comprehensible text messages for an immunization reminder system using Human Factors techniques. Fifty parents completed a structured interview including demographics, technology questions, willingness to receive texts from their child's doctor, and health literacy. Each participant…

Autonomic innervation of immune organs and neuroimmune modulation.

PubMed

Mignini, F; Streccioni, V; Amenta, F

2003-02-01

1. Increasing evidence indicates the occurrence of functional interconnections between immune and nervous systems, although data available on the mechanisms of this bi-directional cross-talking are frequently incomplete and not always focussed on their relevance for neuroimmune modulation. 2. Primary (bone marrow and thymus) and secondary (spleen and lymph nodes) lymphoid organs are supplied with an autonomic (mainly sympathetic) efferent innervation and with an afferent sensory innervation. Anatomical studies have revealed origin, pattern of distribution and targets of nerve fibre populations supplying lymphoid organs. 3. Classic (catecholamines and acetylcholine) and peptide transmitters of neural and non-neural origin are released in the lymphoid microenvironment and contribute to neuroimmune modulation. Neuropeptide Y, substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide represent the neuropeptides most involved in neuroimmune modulation. 4. Immune cells and immune organs express specific receptors for (neuro)transmitters. These receptors have been shown to respond in vivo and/or in vitro to the neural substances and their manipulation can alter immune responses. Changes in immune function can also influence the distribution of nerves and the expression of neural receptors in lymphoid organs. 5. Data on different populations of nerve fibres supplying immune organs and their role in providing a link between nervous and immune systems are reviewed. Anatomical connections between nervous and immune systems represent the structural support of the complex network of immune responses. A detailed knowledge of interactions between nervous and immune systems may represent an important basis for the development of strategies for treating pathologies in which altered neuroimmune cross-talking may be involved.

Control of an automated mobile manipulator using artificial immune system

NASA Astrophysics Data System (ADS)

Deepak, B. B. V. L.; Parhi, Dayal R.

2016-03-01

This paper addresses the coordination and control of a wheeled mobile manipulator (WMM) using artificial immune system. The aim of the developed methodology is to navigate the system autonomously and transport jobs and tools in manufacturing environments. This study integrates the kinematic structures of a four-axis manipulator and a differential wheeled mobile platform. The motion of the developed WMM is controlled by the complete system of parametric equation in terms of joint velocities and makes the robot to follow desired trajectories by the manipulator and platform within its workspace. The developed robot system performs its action intelligently according to the sensed environmental criteria within its search space. To verify the effectiveness of the proposed immune-based motion planner for WMM, simulations as well as experimental results are presented in various unknown environments.

Intrinsic disorder in pathogen effectors: protein flexibility as an evolutionary hallmark in a molecular arms race.

PubMed

Marín, Macarena; Uversky, Vladimir N; Ott, Thomas

2013-09-01

Effector proteins represent a refined mechanism of bacterial pathogens to overcome plants' innate immune systems. These modular proteins often manipulate host physiology by directly interfering with immune signaling of plant cells. Even if host cells have developed efficient strategies to perceive the presence of pathogenic microbes and to recognize intracellular effector activity, it remains an open question why only few effectors are recognized directly by plant resistance proteins. Based on in-silico genome-wide surveys and a reevaluation of published structural data, we estimated that bacterial effectors of phytopathogens are highly enriched in long-disordered regions (>50 residues). These structurally flexible segments have no secondary structure under physiological conditions but can fold in a stimulus-dependent manner (e.g., during protein-protein interactions). The high abundance of intrinsic disorder in effectors strongly suggests positive evolutionary selection of this structural feature and highlights the dynamic nature of these proteins. We postulate that such structural flexibility may be essential for (1) effector translocation, (2) evasion of the innate immune system, and (3) host function mimicry. The study of these dynamical regions will greatly complement current structural approaches to understand the molecular mechanisms of these proteins and may help in the prediction of new effectors.

The development of the immune tissues in marsupial pouch young.

PubMed

Borthwick, Casey R; Young, Lauren J; Old, Julie M

2014-07-01

Current knowledge of the development of the marsupial immune system, particularly in the context of lymphoid tissue development and the appearance of lymphocytes, has been examined and limitations identified. While primary lymphoid tissues like the thymus have been extensively studied, secondary lymphoid tissues such as the spleen and lymph nodes have been examined to a lesser extent, partly due to the difficulty of macroscopically identifying these structures, particularly in very small neonates. In addition, little research has been conducted on the mucosal-associated lymphoid tissues; tissues that directly trap antigens and play an important role in the maturity of adaptive immune responses. Research on the development of the marsupial immune tissues to date serves as a solid foundation for further research, particularly on the mechanisms behind the development of the immune system of marsupials. With the recent sequencing and annotation of whole marsupial genomes, the current wealth of sequence data will be essential in the development of marsupial specific reagents, including antibodies, that are required to widen our specific knowledge of the complex marsupial immune system and its development. © 2014 Wiley Periodicals, Inc.

A global "imaging'' view on systems approaches in immunology.

PubMed

Ludewig, Burkhard; Stein, Jens V; Sharpe, James; Cervantes-Barragan, Luisa; Thiel, Volker; Bocharov, Gennady

2012-12-01

The immune system exhibits an enormous complexity. High throughput methods such as the "-omic'' technologies generate vast amounts of data that facilitate dissection of immunological processes at ever finer resolution. Using high-resolution data-driven systems analysis, causal relationships between complex molecular processes and particular immunological phenotypes can be constructed. However, processes in tissues, organs, and the organism itself (so-called higher level processes) also control and regulate the molecular (lower level) processes. Reverse systems engineering approaches, which focus on the examination of the structure, dynamics and control of the immune system, can help to understand the construction principles of the immune system. Such integrative mechanistic models can properly describe, explain, and predict the behavior of the immune system in health and disease by combining both higher and lower level processes. Moving from molecular and cellular levels to a multiscale systems understanding requires the development of methodologies that integrate data from different biological levels into multiscale mechanistic models. In particular, 3D imaging techniques and 4D modeling of the spatiotemporal dynamics of immune processes within lymphoid tissues are central for such integrative approaches. Both dynamic and global organ imaging technologies will be instrumental in facilitating comprehensive multiscale systems immunology analyses as discussed in this review. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Immunomodulatory properties of carbon nanotubes are able to compensate immune function dysregulation caused by microgravity conditions

NASA Astrophysics Data System (ADS)

Crescio, Claudia; Orecchioni, Marco; Ménard-Moyon, Cécilia; Sgarrella, Francesco; Pippia, Proto; Manetti, Roberto; Bianco, Alberto; Delogu, Lucia Gemma

2014-07-01

Spaceflights lead to dysregulation of the immune cell functionality affecting the expression of activation markers and cytokine production. Short oxidized multi-walled carbon nanotubes functionalized by 1,3-dipolar cycloaddition have been reported to activate immune cells. In this Communication we have performed surface marker assays and multiplex ELISA on primary monocytes and T cells under microgravity. We have discovered that carbon nanotubes, through their immunostimulatory properties, are able to fight spaceflight immune system dysregulations.Spaceflights lead to dysregulation of the immune cell functionality affecting the expression of activation markers and cytokine production. Short oxidized multi-walled carbon nanotubes functionalized by 1,3-dipolar cycloaddition have been reported to activate immune cells. In this Communication we have performed surface marker assays and multiplex ELISA on primary monocytes and T cells under microgravity. We have discovered that carbon nanotubes, through their immunostimulatory properties, are able to fight spaceflight immune system dysregulations. Electronic supplementary information (ESI) available: Experimental section, structures of f-MWCNTs and uptake by human primary immune cells. See DOI: 10.1039/c4nr02711f

Defining dysbiosis and its influence on host immunity and disease

PubMed Central

Petersen, Charisse; Round, June L

2014-01-01

Mammalian immune system development depends on instruction from resident commensal microorganisms. Diseases associated with abnormal immune responses towards environmental and self antigens have been rapidly increasing over the last 50 years. These diseases include inflammatory bowel disease (IBD), multiple sclerosis (MS), type I diabetes (T1D), allergies and asthma. The observation that people with immune mediated diseases house a different microbial community when compared to healthy individuals suggests that pathogenesis arises from improper training of the immune system by the microbiota. However, with hundreds of different microorganisms on our bodies it is hard to know which of these contribute to health and more importantly how? Microbiologists studying pathogenic organisms have long adhered to Koch's postulates to directly relate a certain disease to a specific microbe, raising the question of whether this might be true of commensal–host relationships as well. Emerging evidence supports that rather than one or two dominant organisms inducing host health, the composition of the entire community of microbial residents influences a balanced immune response. Thus, perturbations to the structure of complex commensal communities (referred to as dysbiosis) can lead to deficient education of the host immune system and subsequent development of immune mediated diseases. Here we will overview the literature that describes the causes of dysbiosis and the mechanisms evolved by the host to prevent these changes to community structure. Building off these studies, we will categorize the different types of dysbiosis and define how collections of microorganisms can influence the host response. This research has broad implications for future therapies that go beyond the introduction of a single organism to induce health. We propose that identifying mechanisms to re-establish a healthy complex microbiota after dysbiosis has occurred, a process we will refer to as rebiosis, will be fundamental to treating complex immune diseases. PMID:24798552

Structure of the transporter associated with antigen processing trapped by herpes simplex virus

PubMed Central

Oldham, Michael L; Grigorieff, Nikolaus; Chen, Jue

2016-01-01

The transporter associated with antigen processing (TAP) is an ATP-binding cassette (ABC) transporter essential to cellular immunity against viral infection. Some persistent viruses have evolved strategies to inhibit TAP so that they may go undetected by the immune system. The herpes simplex virus for example evades immune surveillance by blocking peptide transport with a small viral protein ICP47. In this study, we determined the structure of human TAP bound to ICP47 by electron cryo-microscopy (cryo-EM) to 4.0 Å. The structure shows that ICP47 traps TAP in an inactive conformation distinct from the normal transport cycle. The specificity and potency of ICP47 inhibition result from contacts between the tip of the helical hairpin and the apex of the transmembrane cavity. This work provides a clear molecular description of immune evasion by a persistent virus. It also establishes the molecular structure of TAP to facilitate mechanistic studies of the antigen presentation process. DOI: http://dx.doi.org/10.7554/eLife.21829.001 PMID:27935481

Understanding Internal Accountability in Nigeria's Routine Immunization System: Perspectives From Government Officials at the National, State, and Local Levels.

PubMed

Erchick, Daniel J; George, Asha S; Umeh, Chukwunonso; Wonodi, Chizoba

2016-12-10

Routine immunization coverage in Nigeria has remained low, and studies have identified a lack of accountability as a barrier to high performance in the immunization system. Accountability lies at the heart of various health systems strengthening efforts recently launched in Nigeria, including those related to immunization. Our aim was to understand the views of health officials on the accountability challenges hindering immunization service delivery at various levels of government. A semi-structured questionnaire was used to interview immunization and primary healthcare (PHC) officials from national, state, local, and health facility levels in Niger State in north central Nigeria. Individuals were selected to represent a range of roles and responsibilities in the immunization system. The questionnaire explored concepts related to internal accountability using a framework that organizes accountability into three axes based upon how they drive change in the health system. Respondents highlighted accountability challenges across multiple components of the immunization system, including vaccine availability, financing, logistics, human resources, and data management. A major focus was the lack of clear roles and responsibilities both within institutions and between levels of government. Delays in funding, especially at lower levels of government, disrupted service delivery. Supervision occurred less frequently than necessary, and the limited decision space of managers prevented problems from being resolved. Motivation was affected by the inability of officials to fulfill their responsibilities. Officials posited numerous suggestions to improve accountability, including clarifying roles and responsibilities, ensuring timely release of funding, and formalizing processes for supervision, problem solving, and data reporting. Weak accountability presents a significant barrier to performance of the routine immunization system and high immunization coverage in Nigeria. As one stakeholder in ensuring the performance of health systems, routine immunization officials reveal critical areas that need to be prioritized if emerging interventions to improve accountability in routine immunization are to have an effect. © 2017 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Actin Engine in Immunological Synapse

PubMed Central

Piragyte, Indre

2012-01-01

T cell activation and function require physical contact with antigen presenting cells at a specialized junctional structure known as the immunological synapse. Once formed, the immunological synapse leads to sustained T cell receptor-mediated signalling and stabilized adhesion. High resolution microscopy indeed had a great impact in understanding the function and dynamic structure of immunological synapse. Trends of recent research are now moving towards understanding the mechanical part of immune system, expanding our knowledge in mechanosensitivity, force generation, and biophysics of cell-cell interaction. Actin cytoskeleton plays inevitable role in adaptive immune system, allowing it to bear dynamic and precise characteristics at the same time. The regulation of mechanical engine seems very complicated and overlapping, but it enables cells to be very sensitive to external signals such as surface rigidity. In this review, we focus on actin regulators and how immune cells regulate dynamic actin rearrangement process to drive the formation of immunological synapse. PMID:22916042

Animal NLRs provide structural insights into plant NLR function.

PubMed

Bentham, Adam; Burdett, Hayden; Anderson, Peter A; Williams, Simon J; Kobe, Bostjan

2017-03-01

The plant immune system employs intracellular NLRs (nucleotide binding [NB], leucine-rich repeat [LRR]/nucleotide-binding oligomerization domain [NOD]-like receptors) to detect effector proteins secreted into the plant cell by potential pathogens. Activated plant NLRs trigger a range of immune responses, collectively known as the hypersensitive response (HR), which culminates in death of the infected cell. Plant NLRs show structural and functional resemblance to animal NLRs involved in inflammatory and innate immune responses. Therefore, knowledge of the activation and regulation of animal NLRs can help us understand the mechanism of action of plant NLRs, and vice versa. This review provides an overview of the innate immune pathways in plants and animals, focusing on the available structural and biochemical information available for both plant and animal NLRs. We highlight the gap in knowledge between the animal and plant systems, in particular the lack of structural information for plant NLRs, with crystal structures only available for the N-terminal domains of plant NLRs and an integrated decoy domain, in contrast to the more complete structures available for animal NLRs. We assess the similarities and differences between plant and animal NLRs, and use the structural information on the animal NLR pair NAIP/NLRC4 to derive a plausible model for plant NLR activation. Signalling by cooperative assembly formation (SCAF) appears to operate in most innate immunity pathways, including plant and animal NLRs. Our proposed model of plant NLR activation includes three key steps: (1) initially, the NLR exists in an inactive auto-inhibited state; (2) a combination of binding by activating elicitor and ATP leads to a structural rearrangement of the NLR; and (3) signalling occurs through cooperative assembly of the resistosome. Further studies, structural and biochemical in particular, will be required to provide additional evidence for the different features of this model and shed light on the many existing variations, e.g. helper NLRs and NLRs containing integrated decoys. © The Author 2016. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com

P. falciparum Infection Durations and Infectiousness Are Shaped by Antigenic Variation and Innate and Adaptive Host Immunity in a Mathematical Model

PubMed Central

Eckhoff, Philip

2012-01-01

Many questions remain about P. falciparum within-host dynamics, immunity, and transmission–issues that may affect public health campaign planning. These gaps in knowledge concern the distribution of durations of malaria infections, determination of peak parasitemia during acute infection, the relationships among gametocytes and immune responses and infectiousness to mosquitoes, and the effect of antigenic structure on reinfection outcomes. The present model of intra-host dynamics of P. falciparum implements detailed representations of parasite and immune dynamics, with structures based on minimal extrapolations from first-principles biology in its foundations. The model is designed to quickly and readily accommodate gains in mechanistic understanding and to evaluate effects of alternative biological hypothesis through in silico experiments. Simulations follow the parasite from the liver-stage through the detailed asexual cycle to clearance while tracking gametocyte populations. The modeled immune system includes innate inflammatory and specific antibody responses to a repertoire of antigens. The mechanistic focus provides clear explanations for the structure of the distribution of infection durations through the interaction of antigenic variation and innate and adaptive immunity. Infectiousness to mosquitoes appears to be determined not only by the density of gametocytes but also by the level of inflammatory cytokines, which harmonizes an extensive series of study results. Finally, pre-existing immunity can either decrease or increase the duration of infections upon reinfection, depending on the degree of overlap in antigenic repertoires and the strength of the pre-existing immunity. PMID:23028698

Reconciling the Structural Attributes of Avian Antibodies*

PubMed Central

Conroy, Paul J.; Law, Ruby H. P.; Gilgunn, Sarah; Hearty, Stephen; Caradoc-Davies, Tom T.; Lloyd, Gordon; O'Kennedy, Richard J.; Whisstock, James C.

2014-01-01

Antibodies are high value therapeutic, diagnostic, biotechnological, and research tools. Combinatorial approaches to antibody discovery have facilitated access to unique antibodies by surpassing the diversity limitations of the natural repertoire, exploitation of immune repertoires from multiple species, and tailoring selections to isolate antibodies with desirable biophysical attributes. The V-gene repertoire of the chicken does not utilize highly diverse sequence and structures, which is in stark contrast to the mechanism employed by humans, mice, and primates. Recent exploitation of the avian immune system has generated high quality, high affinity antibodies to a wide range of antigens for a number of therapeutic, diagnostic and biotechnological applications. Furthermore, extensive examination of the amino acid characteristics of the chicken repertoire has provided significant insight into mechanisms employed by the avian immune system. A paucity of avian antibody crystal structures has limited our understanding of the structural consequences of these uniquely chicken features. This paper presents the crystal structure of two chicken single chain fragment variable (scFv) antibodies generated from large libraries by phage display against important human antigen targets, which capture two unique CDRL1 canonical classes in the presence and absence of a non-canonical disulfide constrained CDRH3. These structures cast light on the unique structural features of chicken antibodies and contribute further to our collective understanding of the unique mechanisms of diversity and biochemical attributes that render the chicken repertoire of particular value for antibody generation. PMID:24737329

[Clustered regularly interspaced short palindromic repeats: structure, function and application--a review].

PubMed

Cui, Yujun; Li, Yanjun; Yan, Yanfeng; Yang, Ruifu

2008-11-01

CRISPRs (Clustered Regularly Interspaced Short Palindromic Repeats), the basis of spoligotyping technology, can provide prokaryotes with heritable adaptive immunity against phages' invasion. Studies on CRISPR loci and their associated elements, including various CAS (CRISPR-associated) proteins and leader sequences, are still in its infant period. We introduce the brief history', structure, function, bioinformatics research and application of this amazing immunity system in prokaryotic organism for inspiring more scientists to find their interest in this developing topic.

The Interface between Fungal Biofilms and Innate Immunity.

PubMed

Kernien, John F; Snarr, Brendan D; Sheppard, Donald C; Nett, Jeniel E

2017-01-01

Fungal biofilms are communities of adherent cells surrounded by an extracellular matrix. These biofilms are commonly found during infection caused by a variety of fungal pathogens. Clinically, biofilm infections can be extremely difficult to eradicate due to their resistance to antifungals and host defenses. Biofilm formation can protect fungal pathogens from many aspects of the innate immune system, including killing by neutrophils and monocytes. Altered immune recognition during this phase of growth is also evident by changes in the cytokine profiles of monocytes and macrophages exposed to biofilm. In this manuscript, we review the host response to fungal biofilms, focusing on how these structures are recognized by the innate immune system. Biofilms formed by Candida, Aspergillus , and Cryptococcus have received the most attention and are highlighted. We describe common themes involved in the resilience of fungal biofilms to host immunity and give examples of biofilm defenses that are pathogen-specific.

Developmental immunotoxicity of chemicals in rodents and its possible regulatory impact.

PubMed

Hessel, Ellen V S; Tonk, Elisa C M; Bos, Peter M J; van Loveren, Henk; Piersma, Aldert H

2015-01-01

Around 25% of the children in developed countries are affected with immune-based diseases. Juvenile onset diseases such as allergic, inflammatory and autoimmune diseases have shown increasing prevalences in the last decades. The role of chemical exposures in these phenomena is unclear. It is thought that the developmental immune system is more susceptible to toxicants than the mature situation. Developmental immunotoxicity (DIT) testing is nowadays not or minimally included in regulatory toxicology requirements. We reviewed whether developmental immune parameters in rodents would provide relatively sensitive endpoints of toxicity, whose inclusion in regulatory toxicity testing might improve hazard identification and risk assessment of chemicals. For each of the nine reviewed toxicants, the developing immune system was found to be at least as sensitive or more sensitive than the general (developmental) toxicity parameters. Functional immune (antigen-challenged) parameters appear more affected than structural (non-challenged) immune parameters. Especially, antibody responses to immune challenges with keyhole limpet hemocyanine or sheep red blood cells and delayed-type hypersensitivity responses appear to provide sensitive parameters of developmental immune toxicity. Comparison with current tolerable daily intakes (TDI) and their underlying overall no observed adverse effect levels showed that for some of the compounds reviewed, the TDI may need reconsideration based on developmental immune parameters. From these data, it can be concluded that the developing immune system is very sensitive to the disruption of toxicants independent of study design. Consideration of including functional DIT parameters in current hazard identification guidelines and wider application of relevant study protocols is warranted.

An Immunized Aircraft Maneuver Selection System

NASA Technical Reports Server (NTRS)

Karr, Charles L.

2003-01-01

The objective of this project, as stated in the original proposal, was to develop an immunized aircraft maneuver selection (IAMS) system. The IAMS system was to be composed of computational and informational building blocks that resemble structures in natural immune systems. The ultimate goal of the project was to develop a software package that could be flight tested on aircraft models. This report describes the work performed in the first year of what was to have been a two year project. This report also describes efforts that would have been made in the final year to have completed the project, had it been continued for the final year. After introductory material is provided in Section 2, the end-of-year-one status of the effort is discussed in Section 3. The remainder of the report provides an accounting of first year efforts. Section 4 provides background information on natural immune systems while Section 5 describes a generic ar&itecture developed for use in the IAMS. Section 6 describes the application of the architecture to a system identification problem. Finally, Section 7 describes steps necessary for completing the project.

Functional significance of the E loop, a novel motif conserved in the lantibiotic immunity ATP-binding cassette transport systems.

PubMed

Okuda, Ken-ichi; Yanagihara, Sae; Sugayama, Tomomichi; Zendo, Takeshi; Nakayama, Jiro; Sonomoto, Kenji

2010-06-01

Lantibiotics are peptide-derived antibacterial substances produced by some Gram-positive bacteria and characterized by the presence of unusual amino acids, like lanthionines and dehydrated amino acids. Because lantibiotic producers may be attacked by self-produced lantibiotics, they express immunity proteins on the cytoplasmic membrane. An ATP-binding cassette (ABC) transport system mediated by the LanFEG protein complex is a major system in lantibiotic immunity. Multiple-sequence alignment analysis revealed that LanF proteins contain the E loop, a variant of the Q loop, which is a well-conserved motif in the nucleotide-binding domains (NBDs) of general ABC transporters. To elucidate E loop function, we introduced a mutation in the NukF protein, which is involved in the nukacin-ISK-1 immunity system. Amino acid replacement of glutamic acid in the E loop with glutamine (E85Q) resulted in slight decreases in the immunity level and transport activity. Additionally, the E85A mutation severely impaired the immunity level and transport activity. On the other hand, ATPase activities of purified E85Q and E85A mutants were almost similar to that of the wild type. These results suggested that the E loop found in ABC transporters involved in lantibiotic immunity plays a significant role in the function of these transporters, especially in the structural change of transmembrane domains.

Identification of Respiratory Syncytial Virus Nonstructural Protein 2 Residues Essential for Exploitation of the Host Ubiquitin System and Inhibition of Innate Immune Responses.

PubMed

Whelan, Jillian N; Tran, Kim C; van Rossum, Damian B; Teng, Michael N

2016-07-15

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children worldwide. The RSV nonstructural protein 2 (NS2) is a multifunctional protein that primarily acts to antagonize the innate immune system by targeting STAT2 for proteasomal degradation. We investigated the structural determinants of NS2 important for interaction with the host ubiquitin system to degrade STAT2 during infection. We found that NS2 expression enhances ubiquitination of host proteins. Bioinformatics analysis provided a platform for identification of specific residues that limit NS2-induced ubiquitination. Combinations of multiple mutations displayed an additive effect on reducing NS2-induced ubiquitination. Using a reverse genetics system, we generated recombinant RSV (rRSV) containing NS2 ubiquitin mutations, which maintained their effect on ubiquitin expression during infection. Interestingly, STAT2 degradation activity was ablated in the NS2 ubiquitin mutant rRSV. In addition, NS2 ubiquitin mutations decreased rRSV replication, indicating a correlation between NS2's ubiquitin function and antagonism of innate immune signaling to enhance viral replication. Our approach of targeting NS2 residues required for NS2 inhibition of immune responses provides a mechanism for attenuating RSV for vaccine development. RSV has been circulating globally for more than 60 years, causing severe respiratory disease in pediatric, elderly, and immunocompromised populations. Production of a safe, effective vaccine against RSV is a public health priority. The NS2 protein is an effective target for prevention and treatment of RSV due to its antagonistic activity against the innate immune system. However, NS2-deleted RSV vaccine candidates rendered RSV overattenuated or poorly immunogenic. Alternatively, we can modify essential NS2 structural features to marginally limit viral growth while maintaining immune responses, providing the necessary balance between antigenicity and safety required for an effective vaccine. We coupled bioinformatics analysis with reverse genetics to introduce mutations into RSV's negative-sense genome. In this way we constructed rRSV NS2 ubiquitin mutants that limited NS2's ability to antagonize the innate immune system, thereby attenuating rRSV growth and increasing innate immune responses. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Understanding the policy environment for immunization supply chains: Lessons learned from landscape analyses in Uganda and Senegal.

PubMed

Luzze, Henry; Badiane, Ousseynou; Mamadou Ndiaye, El Hadji; Ndiaye, Annette Seck; Atuhaire, Brian; Atuhebwe, Phionah; Guinot, Phillippe; Fry Sosne, Erin; Gueye, Abdoulaye

2017-04-19

As immunization programs around the world undergo rapid change and expansion, supply chain and logistics systems have become strained, making it increasingly challenging for national public health systems to provide reliable, safe, and efficient access to vaccines. Governments and immunization partners have been aware of this problem for several years, and in 2010, the World Health Organization (WHO) launched the Effective Vaccine Management (EVM) process to help countries identify shortcomings in their immunization supply chains and develop plans for systematic improvement. EVM improvement plans now exist in all Gavi-eligible countries plus many middle- and upper-income countries; however, implementation has been slow and in many cases fraught with financial, managerial, structural, and political roadblocks. Recognizing that significant change of any kind requires a supportive policy environment and strong leadership, PATH began working in Uganda and Senegal to landscape the policy environment around immunization and identify relevant policies, administrative and technical roles and responsibilities, and other issues that may be affecting the supply chain for immunization. The policy landscape assessments included a desk review and a series of structured, in-depth interviews with key international, national, and local stakeholders. The findings highlighted a number of critical issues and challenges in both countries that may be preventing supply chains from functioning optimally. These challenges include a need for better coordination and planning between immunization programs and supply chain managers; the need for sufficient, timely and reliable financing for all aspects of immunization programs; the need for high-level managers trained in immunization supply chain management; and an urgent need for better, more timely data for decision-making. Overcoming these challenges will require the involvement of high-level political actors-including ministers of health and finance, parliamentarians, and other officials who have the ability to approve and influence policy, personnel, and structural changes; ensure work plans are backed with adequate resources for implementation; and hold program managers accountable for achieving agreed indicators. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Learning from the US immunization administration].

PubMed

Kamiya, Hajime; Kamiya, Hitoshi

2008-10-01

The US federal government has been providing support to state and local health departments for immunization program since 1920' s. Many government and nongovernment organizations, groups and personnel are involved in the process of the US immunization program. These organizations and groups are moving towards the same direction under the policy of "reducing the incidence of vaccine preventable diseases and to increase the safe usage of vaccines and related biological products". Thus every organization keeps step with the others, which will make states and other local government easier to follow the recommendations. In this review, we will introduce the system and structure of the US immunization administration and indicate why the US has succeeded to decrease vaccine preventable disease with immunization.

Molecular cloning, characterization and expression analysis of TLR9, MyD88 and TRAF6 genes in common carp (Cyprinus carpio)

USDA-ARS?s Scientific Manuscript database

Induction of innate immune pathways is critical for early host defense but there is limited understanding of how teleost fish recognize pathogen molecules and activate these pathways. In mammals, cells of the innate immune system detect pathogenic molecular structures using pattern recognition rece...

Evolutionary divergence and functions of the human interleukin (IL) gene family

PubMed Central

2010-01-01

Cytokines play a very important role in nearly all aspects of inflammation and immunity. The term 'interleukin' (IL) has been used to describe a group of cytokines with complex immunomodulatory functions -- including cell proliferation, maturation, migration and adhesion. These cytokines also play an important role in immune cell differentiation and activation. Determining the exact function of a particular cytokine is complicated by the influence of the producing cell type, the responding cell type and the phase of the immune response. ILs can also have pro- and anti-inflammatory effects, further complicating their characterisation. These molecules are under constant pressure to evolve due to continual competition between the host's immune system and infecting organisms; as such, ILs have undergone significant evolution. This has resulted in little amino acid conservation between orthologous proteins, which further complicates the gene family organisation. Within the literature there are a number of overlapping nomenclature and classification systems derived from biological function, receptor-binding properties and originating cell type. Determining evolutionary relationships between ILs therefore can be confusing. More recently, crystallographic data and the identification of common structural motifs have led to a more accurate classification system. To date, the known ILs can be divided into four major groups based on distinguishing structural features. These groups include the genes encoding the IL1-like cytokines, the class I helical cytokines (IL4-like, γ-chain and IL6/12-like), the class II helical cytokines (IL10-like and IL28-like) and the IL17-like cytokines. In addition, there are a number of ILs that do not fit into any of the above groups, due either to their unique structural features or lack of structural information. This suggests that the gene family organisation may be subject to further change in the near future. PMID:21106488

Relative sensitivity of developmental and immune parameters in juvenile versus adult male rats after exposure to di(2-ethylhexyl) phthalate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tonk, Elisa C.M., E-mail: ilse.tonk@rivm.nl; Laboratory for Health Protection Research, National Institute for Public Health and the Environment; Verhoef, Aart

The developing immune system displays a relatively high sensitivity as compared to both general toxicity parameters and to the adult immune system. In this study we have performed such comparisons using di(2-ethylhexyl) phthalate (DEHP) as a model compound. DEHP is the most abundant phthalate in the environment and perinatal exposure to DEHP has been shown to disrupt male sexual differentiation. In addition, phthalate exposure has been associated with immune dysfunction as evidenced by effects on the expression of allergy. Male wistar rats were dosed with corn oil or DEHP by gavage from postnatal day (PND) 10–50 or PND 50–90 atmore » doses between 1 and 1000 mg/kg/day. Androgen-dependent organ weights showed effects at lower dose levels in juvenile versus adult animals. Immune parameters affected included TDAR parameters in both age groups, NK activity in juvenile animals and TNF-α production by adherent splenocytes in adult animals. Immune parameters were affected at lower dose levels compared to developmental parameters. Overall, more immune parameters were affected in juvenile animals compared to adult animals and effects were observed at lower dose levels. The results of this study show a relatively higher sensitivity of juvenile versus adult rats. Furthermore, they illustrate the relative sensitivity of the developing immune system in juvenile animals as compared to general toxicity and developmental parameters. This study therefore provides further argumentation for performing dedicated developmental immune toxicity testing as a default in regulatory toxicology. -- Highlights: ► In this study we evaluate the relative sensitivities for DEHP induced effects. ► Results of this study demonstrate the age-dependency of DEHP toxicity. ► Functional immune parameters were more sensitive than structural immune parameters. ► Immune parameters were affected at lower dose levels than developmental parameters. ► Findings demonstrate the susceptibility of the developing immune system for DEHP.« less

Inorganic nanoparticles and the immune system: detection, selective activation and tolerance

NASA Astrophysics Data System (ADS)

Bastús, Neus G.; Sánchez-Tilló, Ester; Pujals, Silvia; Comenge, Joan; Giralt, Ernest; Celada, Antonio; Lloberas, Jorge; Puntes, Victor F.

2012-03-01

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

Overview of Basic Immunology for Clinical Investigators.

PubMed

Stephen, Bettzy; Hajjar, Joud

2017-01-01

Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the cross talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.

Construction of recombinant Lactobacillus casei efficiently surface displayed and secreted porcine parvovirus VP2 protein and comparison of the immune responses induced by oral immunization.

PubMed

Yigang, X U; Yijing, L I

2008-05-01

Lactobacillus casei ATCC 393 was selected as a bacterial carrier for the development of mucosal vaccine against porcine parvovirus (PPV) infection. The PPV major structural polypeptide VP2 was used as the model parvovirus antigen. Two inducible expression systems, namely pPG611.1 of the cell-surface expression system and pPG612.1 of the secretion expression system based on the xylose operon promoter were used to express the VP2 protein. The immunogenicity of recombinant strains producing VP2 protein in two cellular locations, cell-surface exposed and secreted, was compared to each other by immunizing mice through the intragastric administration. The two types of constructs were able to induce strong specific immune responses against VP2 via intragastric administration and maximum titres of IgA and IgG were attained on days 46 post oral immunization, while the highest antibody levels were obtained with the strain producing the VP2 protein in extracellular milieu. The induced antibodies demonstrated neutralizing effects on PPV infection.

Consequences of contamination of the spacecraft environment: immunologic consequences

NASA Technical Reports Server (NTRS)

Shearer, W. T.

2001-01-01

Long-term space voyages pose numerous known and unknown health hazards, to the human immune system. Well-studied clinical examples of secondary immunodeficiencies created on Earth, lead one to predict that the conditions of prolonged space flight would weaken the human immune responses that normally hold infection and cancer in check. From evidence gathered from humans flown for prolonged periods in space and from human models of space flight studied on Earth it is reasonable to suspect that space travelers to the planet Mars would experience a weakening of immunity. Subtle defects of immune cell structure and function have been observed in astronauts, such as weakening of specific T-lymphocyte recall of specific antigens. Ground-based models also have demonstrated alterations of immune function, such as the elevation of neuroendocrine immune system messengers, interleukin-6, and soluble tumor necrosis factor-alpha receptor in sleep deprivation. Since severe immune compromise the clinical consequences of reactivation of latent virus infections and the development of cancer, has yet to be seen in space flight or in the Earth models, it is extremely important to begin to quantify early changes in immunity to predict the development of immune system collapse with poor clinical outcomes. This approach is designed to validate a number of surrogate markers that will predict trouble ahead. Inherent in this research is the development of countermeasures to reduce the risks of infection and cancer in the first humans going to Mars.

Federal immunization policy and funding: a history of responding to crises.

PubMed

Johnson, K A; Sardell, A; Richards, B

2000-10-01

This article outlines the history of federal immunization policy and funding, with a focus on discretionary federal funding under Section 317 of the Public Health Service Act, paying particular attention to the role of Congress in shaping the program in the past 2 decades. This review of funding trends and initiatives indicates that when both a presidential administration and key congressional actors viewed immunization as a priority and made sufficient funds available to support the public health delivery system and its infrastructure, coverage levels would continue to rise and disease levels continue to decline. From the beginning, immunization financing was explicitly structured as a federal-state-private-sector partnership. Section 317 program's statute has not changed much in 35 years, despite significant changes to the health care delivery system, other federal immunization activities, and rates of immunization coverage. Although the creation and implementation of the Vaccines for Children (VFC) program in the mid-1990s resulted in some congressional deliberations over immunization policies, no explicit restructuring of the 317 program occurred as a result. The Section 317 program retains its traditional authority and mission to address urgent needs, sustain public delivery systems, and provide funds for purchase of vaccines. The question remains whether the resources to sustain progress in immunization can be secured during times with no crisis, to ensure constant "readiness" in immunization (as in defense), or whether another epidemic must occur before the federal government is willing to commit optimal resources.

78 FR 26794 - Prospective Grant of Exclusive License: Use of Oligodeoxynucleotide as Neuroprotectants in...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-08

... following ischemic damage to the central nervous system. Structural differences between various ODNs may... ODNs mimic signals of invading pathogens. ODN motifs trigger immune system responses via Toll-like...

Human NOD2 Recognizes Structurally Unique Muramyl Dipeptides from Mycobacterium leprae

PubMed Central

Schenk, Mirjam; Mahapatra, Sebabrata; Le, Phuonganh; Kim, Hee Jin; Choi, Aaron W.; Brennan, Patrick J.; Belisle, John T.

2016-01-01

The innate immune system recognizes microbial pathogens via pattern recognition receptors. One such receptor, NOD2, via recognition of muramyl dipeptide (MDP), triggers a distinct network of innate immune responses, including the production of interleukin-32 (IL-32), which leads to the differentiation of monocytes into dendritic cells (DC). NOD2 has been implicated in the pathogenesis of human leprosy, yet it is not clear whether Mycobacterium leprae, which has a distinct MDP structure, can activate this pathway. We investigated the effect of MDP structure on the innate immune response, finding that infection of monocytes with M. leprae induces IL-32 and DC differentiation in a NOD2-dependent manner. The presence of the proximal l-Ala instead of Gly in the common configuration of the peptide side chain of M. leprae did not affect recognition by NOD2 or cytokine production. Furthermore, amidation of the d-Glu residue did not alter NOD2 activation. These data provide experimental evidence that NOD2 recognizes naturally occurring structural variants of MDP. PMID:27297389

Histomorphology and innate immunity during the progression of osteoarthritis: Does synovitis affect cartilage degradation?

PubMed

Wang, Huan; Wang, Qingguo; Yang, Meijuan; Yang, Lili; Wang, Weili; Ding, Haobin; Zhang, Dong; Xu, Jing; Tang, Xuezhang; Ding, Haitao; Wang, Qingfu

2018-02-01

Osteoarthritis (OA) is a common chronic degenerative disease that affects all joints. At present, the pathological processes and mechanisms of OA are still unclear. Innate immunity, a key player in damage to the structure of the joint and the mechanism by which the host attempts to repair OA, affects all pathological stages of the disease. In the present study, our aim was to assess changes in innate immunity during the pathological processes of OA in articular cartilage (AC) and the synovial membrane (SM), which are the major structures in joints, and to systematically examine the histological changes in AC and SM in mild, moderate and severe cases of OA, in order to further speculate about the manner in which the interactions of AC and SM are facilitated by innate immunity. Histological methods (including HE and Safranin O-fast green staining), immunofluorescent double staining, TUNEL stain, and Western blots were used to assess the morphological changes within AC and SM tissues in healthy and mild, moderate, or severe OA rats. Our results showed that the damage to AC and SM within the joints progressively worsened in different degrees during the course of the disease, and that the innate immune system was closely involved in the AC and SM during each stage of OA. These findings also confirmed that SM may affect the pathological changes in AC through the innate immune system, and therefore affect the progress of OA. © 2017 Wiley Periodicals, Inc.

Modular Design Features of a Peptide Amphiphile Micelle Vaccine Platform and Their Impact on an Immune Response

NASA Astrophysics Data System (ADS)

Barrett, John Christopher

Inducing a strong and specific immune response is the hallmark of a successful vaccine. Nanoparticles have emerged as promising vaccine delivery devices to discover and elicit immune responses. Modular platforms are attractive for their engineerability and broad potential applications. Fine-tuning a nanoparticle vaccine to create an immune response with specific antibody and other cellular responses is influenced by many factors such as shape, size and composition. Peptide amphiphile micelles are a unique biomaterials platform that can function as a modular vaccine delivery system, enabling control over many of these important factors. Peptide amphiphiles (PAs) consist of a hydrophilic peptide antigen conjugated to a hydrophobic lipid tail. The PAs then self-assemble into micelles, with the micelle characteristics determined by the chemical composition of the PA and micelle preparation methods. PA micelles contain a large design space, so it is important to have a basic understanding of how each design feature can affect the platform's interaction with the immune system. In this dissertation, the structure, composition, and biodistribution properties of PA micelles are evaluated for their ability to impact an immune response against a Group A Streptococcus B cell antigen (J8). Through structural design and physical characterization, micelles are shown to self-assemble into either short rod-like or long cylindrical shapes. Analyzing these shape effects on the immune response showed that cylindrical micelles induced higher antibody titers than rod-like micelles, providing evidence that the cylindrical micelle shape is important to induce immune responses and a possible mechanism of action. Shape was also seen to impact the activation profile of dendritic cells, B cells and T cells. Assembly into cylindrical micelles also stabilizes the secondary structure of peptide antigens, which may impact the immune response raised. In composition, the hydrophobic/hydrophilic interface of PA micelles enabled the precise entrapment of amphiphilic adjuvants which were found to not alter micelle formation or shape. These heterogeneous micelles significantly enhanced murine antibody responses when compared to animals vaccinated with non-adjuvanted micelles or soluble J8 peptide supplemented with a classical adjuvant. PAs were also shown to traffic more efficiently to the lymph node than free peptide. Characterization of these design features and their impact on an immune response provides a valuable foundation of knowledge to apply when expanding the peptide amphiphile micelle platform to other vaccine applications.

Stress and the psyche-brain-immune network in psychiatric diseases based on psychoneuroendocrineimmunology: a concise review.

PubMed

Bottaccioli, Anna Giulia; Bottaccioli, Francesco; Minelli, Andrea

2018-05-15

In the last decades, psychoneuroendocrineimmunology research has made relevant contributions to the fields of neuroscience, psychobiology, epigenetics, molecular biology, and clinical research by studying the effect of stress on human health and highlighting the close interrelations between psyche, brain, and bodily systems. It is now well recognized that chronic stress can alter the physiological cross-talk between brain and biological systems, leading to long-lasting maladaptive effects (allostatic overload) on the nervous, immune, endocrine, and metabolic systems, which compromises stress resiliency and health. Stressful conditions in early life have been associated with profound alterations in cortical and subcortical brain regions involved in emotion regulation and the salience network, showing relevant overlap with different psychiatric conditions. This paper provides a summary of the available literature concerning the notable effects of stress on the brain and immune system. We highlight the role of epigenetics as a mechanistic pathway mediating the influences of the social and physical environment on brain structure and connectivity, the immune system, and psycho-physical health in psychiatric diseases. We also summarize the evidence regarding the effects of stress management techniques (mainly psychotherapy and meditation practice) on clinical outcomes, brain neurocircuitry, and immune-inflammatory network in major psychiatric diseases. © 2018 New York Academy of Sciences.

Receptor signaling clusters in the immune synapse(in eng)

DOE PAGES

Dustin, Michael L.; Groves, Jay T.

2012-02-23

Signaling processes between various immune cells involve large-scale spatial reorganization of receptors and signaling molecules within the cell-cell junction. These structures, now collectively referred to as immune synapses, interleave physical and mechanical processes with the cascades of chemical reactions that constitute signal transduction systems. Molecular level clustering, spatial exclusion, and long-range directed transport are all emerging as key regulatory mechanisms. The study of these processes is drawing researchers from physical sciences to join the effort and represents a rapidly growing branch of biophysical chemistry. Furthermore, recent advances in physical and quantitative analyses of signaling within the immune synapses are reviewedmore » here.« less

Receptor signaling clusters in the immune synapse (in eng)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dustin, Michael L.; Groves, Jay T.

2012-02-23

Signaling processes between various immune cells involve large-scale spatial reorganization of receptors and signaling molecules within the cell-cell junction. These structures, now collectively referred to as immune synapses, interleave physical and mechanical processes with the cascades of chemical reactions that constitute signal transduction systems. Molecular level clustering, spatial exclusion, and long-range directed transport are all emerging as key regulatory mechanisms. The study of these processes is drawing researchers from physical sciences to join the effort and represents a rapidly growing branch of biophysical chemistry. Furthermore, recent advances in physical and quantitative analyses of signaling within the immune synapses are reviewedmore » here.« less

A new synthesis for antibody-mediated immunity

PubMed Central

Casadevall, Arturo; Pirofski, Liise-anne

2013-01-01

The view that immunoglobulins function largely by potentiating neutralization, cytotoxicity or phagocytosis is being replaced by a new synthesis whereby antibodies participate in all aspects of the immune response, from protecting the host at the earliest time of encounter with a microbe to later challenges. Perhaps the most transformative concept is that immunoglobulins manifest emergent properties, from their structure and function as individual molecules to their interactions with microbial targets and the host immune system. Given that emergent properties are neither reducible to first principles nor predictable, there is a need for new conceptual approaches for understanding antibody function and mechanisms of antibody immunity. PMID:22179281

Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity.

PubMed

Murphy, J E; Robert, C; Kupper, T S

2000-03-01

As our primary interface with the environment, the skin is constantly subjected to injury and invasion by pathogens. The fundamental force driving the evolution of the immune system has been the need to protect the host against overwhelming infection. The ability of T and B cells to recombine antigen receptor genes during development provides an efficient, flexible, and powerful immune system with nearly unlimited specificity for antigen. The capacity to expand subsets of antigen-specific lymphocytes that become activated by environmental antigens (memory response) is termed "acquired" immunity. Immunologic memory, although a fundamental aspect of mammalian biology, is a relatively recent evolutionary event that permits organisms to live for years to decades. "Innate" immunity, mediated by genes that remain in germ line conformation and encode for proteins that recognize conserved structural patterns on microorganisms, is a much more ancient system of host defense. Defensins and other antimicrobial peptides, complement and opsonins, and endocytic receptors are all considered components of the innate immune system. None of these, however, are signal-transducing receptors. Most recently, a large family of cell surface receptors that mediate signaling through the NF-kappaB transcription factor has been identified. This family of proteins shares striking homology with plant and Drosophila genes that mediate innate immunity. In mammals, this family includes the type I interleukin-1 receptor, the interleukin-18 receptor, and a growing family of Toll-like receptors, two of which were recently identified as signal-transducing receptors for bacterial endotoxin. In this review, we discuss how interleukin-1 links the innate and acquired immune systems to provide synergistic host defense activities in skin.

Immune Recognition of Fungal Polysaccharides.

PubMed

Snarr, Brendan D; Qureshi, Salman T; Sheppard, Donald C

2017-08-28

The incidence of fungal infections has dramatically increased in recent years, in large part due to increased use of immunosuppressive medications, as well as aggressive medical and surgical interventions that compromise natural skin and mucosal barriers. There are relatively few currently licensed antifungal drugs, and rising resistance to these agents has led to interest in the development of novel preventative and therapeutic strategies targeting these devastating infections. One approach to combat fungal infections is to augment the host immune response towards these organisms. The polysaccharide-rich cell wall is the initial point of contact between fungi and the host immune system, and therefore, represents an important target for immunotherapeutic approaches. This review highlights the advances made in our understanding of the mechanisms by which the immune system recognizes and interacts with exopolysaccharides produced by four of the most common fungal pathogens: Aspergillus fumigatus , Candida albicans , Cryptococcus neoformans , and Histoplasma capsulatum . Work to date suggests that inner cell wall polysaccharides that play an important structural role are the most conserved across diverse members of the fungal kingdom, and elicit the strongest innate immune responses. The immune system senses these carbohydrates through receptors, such as lectins and complement proteins. In contrast, a greater diversity of polysaccharides is found within the outer cell walls of pathogenic fungi. These glycans play an important role in immune evasion, and can even induce anti-inflammatory host responses. Further study of the complex interactions between the host immune system and the fungal polysaccharides will be necessary to develop more effective therapeutic strategies, as well as to explore the use of immunosuppressive polysaccharides as therapeutic agents to modulate inflammation.

Early-Life Food Nutrition, Microbiota Maturation and Immune Development Shape Life-Long Health.

PubMed

Zhou, Xiaoli; Du, Lina; Shi, Ronghua; Chen, Zhidong; Zhou, Yiming; Li, Zongjie

2018-06-06

The current knowledge about early-life nutrition and environmental factors that affect the interaction between the symbiotic microbiota and the host immune system has demonstrated novel regulatory target for treating allergic diseases, autoimmune disorders and metabolic syndrome. Various kinds of food nutrients (such as dietary fiber, starch, polyphenols and proteins) can provide energy resources for both intestinal microbiota and the host. The indigestible food components are fermented by the indigenous gut microbiota to produce diverse metabolites, including short-chain fatty acids, bile acids and trimethylamine-N-oxide, which can regulate the host metabolized physiology, immunity homeostasis and health state. Therefore it is commonly believed early-life perturbation of the microbial community structure and the dietary nutrition interference on the child mucosal immunity contribute to the whole life susceptibility to chronic diseases. In all, the combined interrelationship between food ingredients nutrition, intestinal microbiota configurations and host system immunity provides new therapeutic targets to treat various kinds of pathogenic inflammations and chronic diseases.

Vesicular trafficking of immune mediators in human eosinophils revealed by immunoelectron microscopy.

PubMed

Melo, Rossana C N; Weller, Peter F

2016-10-01

Electron microscopy (EM)-based techniques are mostly responsible for our current view of cell morphology at the subcellular level and continue to play an essential role in biological research. In cells from the immune system, such as eosinophils, EM has helped to understand how cells package and release mediators involved in immune responses. Ultrastructural investigations of human eosinophils enabled visualization of secretory processes in detail and identification of a robust, vesicular trafficking essential for the secretion of immune mediators via a non-classical secretory pathway associated with secretory (specific) granules. This vesicular system is mainly organized as large tubular-vesicular carriers (Eosinophil Sombrero Vesicles - EoSVs) actively formed in response to cell activation and provides a sophisticated structural mechanism for delivery of granule-stored mediators. In this review, we highlight the application of EM techniques to recognize pools of immune mediators at vesicular compartments and to understand the complex secretory pathway within human eosinophils involved in inflammatory and allergic responses. Copyright © 2016 Elsevier Inc. All rights reserved.

Exosomes and Immune Response in Cancer: Friends or Foes?

PubMed

Barros, Francisco M; Carneiro, Fatima; Machado, Jose C; Melo, Sónia A

2018-01-01

Exosomes are a type of extracellular vesicle whose study has grown exponentially in recent years. This led to the understanding that these structures, far from being inert waste by-products of cellular functioning, are active players in intercellular communication mechanisms, including in the interactions between cancer cells and the immune system. The deep comprehension of the crosstalk between tumors and the immune systems of their hosts has gained more and more importance, as immunotherapeutic techniques have emerged as viable options for several types of cancer. In this review, we present a comprehensive, updated, and elucidative review of the current knowledge on the functions played by the exosomes in this crosstalk. The roles of these vesicles in tumor antigen presentation, immune activation, and immunosuppression are approached as the relevant interactions between exosomes and the complement system. The last section of this review is reserved for the exploration of the results from the first phase I to II clinical trials of exosomes-based cell-free cancer vaccines.

The evaluation of a standardized call/recall system for childhood immunizations in Wandsworth, England.

PubMed

Atchison, Christina; Zvoc, Miro; Balakrishnan, Ravikumar

2013-06-01

To improve uptake of childhood immunizations in Wandsworth we developed a standardized call/recall system based on parents being sent three reminders and defaulters being referred to a Health Visitor. Thirty-two out of 44 primary care practices in the area implemented the intervention in September 2011. The aim of this study was to evaluate the implementation, delivery and impact on immunization uptake of the new call/recall system. To assess implementation and delivery, a mixed method approach was used including qualitative (structured interviews) and quantitative (data collected at three months post-implementation) assessment. To assess the impact, we used Student's t test to compare the difference in immunization uptake rates between intervention and non-intervention practices before and after implementation. The call/recall system was viewed positively by both parents and staff. Most children due or overdue immunizations were successfully captured by the 1st invitation reminder. After three invitations, between 87.3 % (MMR1) and 92.2 % (pre-school booster) of children identified as due or overdue immunizations successfully responded. Prior to implementation there was no difference in uptake rates between intervention and non-intervention practices. Post-implementation uptake rates for DTaP/IPV/Hib, MMR1, MMR2 and the pre-school booster were significantly greater in the intervention practices. Similar findings were seen for PCV and Hib/MenC boosters, although the differences were not statistically significant at the 5 % level. Following the successful implementation of a standardized call/recall system in Wandsworth, other regions or primary care practices may wish to consider introducing a similar system to help improve their immunization coverage levels.

Coxiella burnetii Lipopolysaccharide: What Do We Know?

PubMed Central

Abnave, Prasad; Muracciole, Xavier; Ghigo, Eric

2017-01-01

A small gram-negative bacterium, Coxiella burnetii (C. burnetii), is responsible for a zoonosis called Q fever. C. burnetii is an intracellular bacterium that can survive inside microbicidal cells like monocytes and macrophages by hijacking several functions of the immune system. Among several virulence factors, the lipopolysaccharide (LPS) of C. burnetii is one of the major factors involved in this immune hijacking because of its atypical composition and structure. Thus, the aim of this mini-review is to summarize the repressive effects of C. burnetii LPS on the antibacterial immunity of cells. PMID:29168790

Modulation of immune responses of Rhynchophorus ferrugineus (Insecta: Coleoptera) induced by the entomopathogenic nematode Steinernema carpocapsae (Nematoda: Rhabditida).

PubMed

Mastore, Maristella; Arizza, Vincenzo; Manachini, Barbara; Brivio, Maurizio F

2015-12-01

Aim of this study was to investigate relationships between the red palm weevil (RPW) Rhynchophorus ferrugineus (Olivier) and the entomopathogenic nematode Steinernema carpocapsae (EPN); particularly, the work was focused on the immune response of the insect host in naive larvae and after infection with the EPN. Two main immunological processes have been addressed: the activity and modulation of host prophenoloxidase-phenoloxidase (proPO) system, involved in melanization of not-self and hemocytes recognition processes responsible for not-self encapsulation. Moreover, immune depressive and immune evasive strategies of the parasite have been investigated. Our results suggest that RPW possess an efficient immune system, however in the early phase of infection, S. carpocapsae induces a strong inhibition of the host proPO system. In addition, host cell-mediated mechanisms of encapsulation, are completely avoided by the parasite, the elusive strategies of S. carpocapsae seem to be related to the structure of its body-surface, since induced alterations of the parasite cuticle resulted in the loss of its mimetic properties. S. carpocapsae before the release of its symbiotic bacteria, depress and elude RPW immune defenses, with the aim to arrange a favorable environment for its bacteria responsible of the septicemic death of the insect target. © 2014 Institute of Zoology, Chinese Academy of Sciences.

Vesicular trafficking of immune mediators in human eosinophils revealed by immunoelectron microscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Melo, Rossana C.N., E-mail: rossana.melo@ufjf.edu.br; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 943, Boston, MA 02215; Weller, Peter F.

Electron microscopy (EM)-based techniques are mostly responsible for our current view of cell morphology at the subcellular level and continue to play an essential role in biological research. In cells from the immune system, such as eosinophils, EM has helped to understand how cells package and release mediators involved in immune responses. Ultrastructural investigations of human eosinophils enabled visualization of secretory processes in detail and identification of a robust, vesicular trafficking essential for the secretion of immune mediators via a non-classical secretory pathway associated with secretory (specific) granules. This vesicular system is mainly organized as large tubular-vesicular carriers (Eosinophil Sombreromore » Vesicles – EoSVs) actively formed in response to cell activation and provides a sophisticated structural mechanism for delivery of granule-stored mediators. In this review, we highlight the application of EM techniques to recognize pools of immune mediators at vesicular compartments and to understand the complex secretory pathway within human eosinophils involved in inflammatory and allergic responses. - Highlights: • Application of EM to understand the complex secretory pathway in human eosinophils. • EM techniques reveal an active vesicular system associated with secretory granules. • Tubular vesicles are involved in the transport of granule-derived immune mediators.« less

Regulation of humoral immunity by complement.

PubMed

Carroll, Michael C; Isenman, David E

2012-08-24

The complement system of innate immunity is important in regulating humoral immunity largely through the complement receptor CR2, which forms a coreceptor on B cells during antigen-induced activation. However, CR2 also retains antigens on follicular dendritic cells (FDCs). Display of antigen on FDCs is critical for clonal selection and affinity maturation of activated B cells. This review will discuss the role of complement in adaptive immunity in general with a focus on the interplay between CR2-associated antigen on B cells with CR2 expressed on FDCs. This latter interaction provides an opportunity for memory B cells to sample antigen over prolonged periods. The cocrystal structure of CR2 with its ligand C3d provides insight into how the complement system regulates access of antigen by B cells with implications for therapeutic manipulations to modulate aberrant B cell responses in the case of autoimmunity. Copyright © 2012 Elsevier Inc. All rights reserved.

Efforts to monitor Global progress on individual and community demand for immunization: Development of definitions and indicators for the Global Vaccine Action Plan Strategic Objective 2.

PubMed

Hickler, Benjamin; MacDonald, Noni E; Senouci, Kamel; Schuh, Holly B

2017-06-16

The Second Strategic Objective of the Global Vaccine Action Plan, "individuals and communities understand the value of vaccines and demand immunization as both their right and responsibility", differs from the other five in that it does not focus on supply-side aspects of immunization programs but rather on public demand for vaccines and immunization services. This commentary summarizes the work (literature review, consultations with experts, and with potential users) and findings of the UNICEF/World Health Organization Strategic Objective 2 informal Working Group on Vaccine Demand, which developed a definition for demand and indicators related to Strategic Objective 2. Demand for vaccines and vaccination is a complex concept that is not external to supply systems but rather encompasses the interaction between human behaviors and system structure and dynamics. Copyright © 2017. Published by Elsevier Ltd.

Immune Receptors and Co-receptors in Antiviral Innate Immunity in Plants.

PubMed

Gouveia, Bianca C; Calil, Iara P; Machado, João Paulo B; Santos, Anésia A; Fontes, Elizabeth P B

2016-01-01

Plants respond to pathogens using an innate immune system that is broadly divided into PTI (pathogen-associated molecular pattern- or PAMP-triggered immunity) and ETI (effector-triggered immunity). PTI is activated upon perception of PAMPs, conserved motifs derived from pathogens, by surface membrane-anchored pattern recognition receptors (PRRs). To overcome this first line of defense, pathogens release into plant cells effectors that inhibit PTI and activate effector-triggered susceptibility (ETS). Counteracting this virulence strategy, plant cells synthesize intracellular resistance (R) proteins, which specifically recognize pathogen effectors or avirulence (Avr) factors and activate ETI. These coevolving pathogen virulence strategies and plant resistance mechanisms illustrate evolutionary arms race between pathogen and host, which is integrated into the zigzag model of plant innate immunity. Although antiviral immune concepts have been initially excluded from the zigzag model, recent studies have provided several lines of evidence substantiating the notion that plants deploy the innate immune system to fight viruses in a manner similar to that used for non-viral pathogens. First, most R proteins against viruses so far characterized share structural similarity with antibacterial and antifungal R gene products and elicit typical ETI-based immune responses. Second, virus-derived PAMPs may activate PTI-like responses through immune co-receptors of plant PTI. Finally, and even more compelling, a viral Avr factor that triggers ETI in resistant genotypes has recently been shown to act as a suppressor of PTI, integrating plant viruses into the co-evolutionary model of host-pathogen interactions, the zigzag model. In this review, we summarize these important progresses, focusing on the potential significance of antiviral immune receptors and co-receptors in plant antiviral innate immunity. In light of the innate immune system, we also discuss a newly uncovered layer of antiviral defense that is specific to plant DNA viruses and relies on transmembrane receptor-mediated translational suppression for defense.

A non-classical phase diagram for virus-bacterial co-evolution mediated by CRISPR

NASA Astrophysics Data System (ADS)

Han, Pu; Deem, Michael

CRISPR is a newly discovered prokaryotic immune system. Bacteria and archaea with this system incorporate genetic material from invading viruses into their genomes, providing protection against future infection by similar viruses. Due to the cost of CRISPR, bacteria can lose the acquired immunity. We will show an intriguing phase diagram of the virus extinction probability, which when the rate of losing the acquired immunity is small, is more complex than that of the classic predator-prey model. As the CRISPR incorporates genetic material, viruses are under pressure to evolve to escape the recognition by CRISPR, and this co-evolution leads to a non-trivial phase structure that cannot be explained by the classical predator-prey model.

Microbiota and Mucosal Immunity in Amphibians

PubMed Central

Colombo, Bruno M.; Scalvenzi, Thibault; Benlamara, Sarah; Pollet, Nicolas

2015-01-01

We know that animals live in a world dominated by bacteria. In the last 20 years, we have learned that microbes are essential regulators of mucosal immunity. Bacteria, archeas, and viruses influence different aspects of mucosal development and function. Yet, the literature mainly covers findings obtained in mammals. In this review, we focus on two major themes that emerge from the comparative analysis of mammals and amphibians. These themes concern: (i) the structure and functions of lymphoid organs and immune cells in amphibians, with a focus on the gut mucosal immune system; and (ii) the characteristics of the amphibian microbiota and its influence on mucosal immunity. Lastly, we propose to use Xenopus tadpoles as an alternative small-animal model to improve the fundamental knowledge on immunological functions of gut microbiota. PMID:25821449

Spectroscopic techniques to study the immune response in human saliva

NASA Astrophysics Data System (ADS)

Nepomnyashchaya, E.; Savchenko, E.; Velichko, E.; Bogomaz, T.; Aksenov, E.

2018-01-01

Studies of the immune response dynamics by means of spectroscopic techniques, i.e., laser correlation spectroscopy and fluorescence spectroscopy, are described. The laser correlation spectroscopy is aimed at measuring sizes of particles in biological fluids. The fluorescence spectroscopy allows studying of the conformational and other structural changings in immune complex. We have developed a new scheme of a laser correlation spectrometer and an original signal processing algorithm. We have suggested a new fluorescence detection scheme based on a prism and an integrating pin diode. The developed system based on the spectroscopic techniques allows studies of complex process in human saliva and opens some prospects for an individual treatment of immune diseases.

3-Dimesional Structure of Factor D

NASA Technical Reports Server (NTRS)

2004-01-01

The trauma caused by the open heart surgery often triggers massive inflammation because the immune system overreacts. Factor D, the protein which plays a key role in the biological steps that activate this immune response prevents the imune system from inappropriately rurning out of control, allowing the patient to recover more rapidly. Factor D blockers, with their great potential to alleviate the complication of inflammation associated with heart surgery, are now being developed for clinical trials. These new drugs, developed from space research, should be commercially available as soon as year 2001.

Optimization of protein-protein docking for predicting Fc-protein interactions.

PubMed

Agostino, Mark; Mancera, Ricardo L; Ramsland, Paul A; Fernández-Recio, Juan

2016-11-01

The antibody crystallizable fragment (Fc) is recognized by effector proteins as part of the immune system. Pathogens produce proteins that bind Fc in order to subvert or evade the immune response. The structural characterization of the determinants of Fc-protein association is essential to improve our understanding of the immune system at the molecular level and to develop new therapeutic agents. Furthermore, Fc-binding peptides and proteins are frequently used to purify therapeutic antibodies. Although several structures of Fc-protein complexes are available, numerous others have not yet been determined. Protein-protein docking could be used to investigate Fc-protein complexes; however, improved approaches are necessary to efficiently model such cases. In this study, a docking-based structural bioinformatics approach is developed for predicting the structures of Fc-protein complexes. Based on the available set of X-ray structures of Fc-protein complexes, three regions of the Fc, loosely corresponding to three turns within the structure, were defined as containing the essential features for protein recognition and used as restraints to filter the initial docking search. Rescoring the filtered poses with an optimal scoring strategy provided a success rate of approximately 80% of the test cases examined within the top ranked 20 poses, compared to approximately 20% by the initial unrestrained docking. The developed docking protocol provides a significant improvement over the initial unrestrained docking and will be valuable for predicting the structures of currently undetermined Fc-protein complexes, as well as in the design of peptides and proteins that target Fc. Copyright © 2016 John Wiley & Sons, Ltd.

Sensitivity Analysis of an ENteric Immunity SImulator (ENISI)-Based Model of Immune Responses to Helicobacter pylori Infection

PubMed Central

Alam, Maksudul; Deng, Xinwei; Philipson, Casandra; Bassaganya-Riera, Josep; Bisset, Keith; Carbo, Adria; Eubank, Stephen; Hontecillas, Raquel; Hoops, Stefan; Mei, Yongguo; Abedi, Vida; Marathe, Madhav

2015-01-01

Agent-based models (ABM) are widely used to study immune systems, providing a procedural and interactive view of the underlying system. The interaction of components and the behavior of individual objects is described procedurally as a function of the internal states and the local interactions, which are often stochastic in nature. Such models typically have complex structures and consist of a large number of modeling parameters. Determining the key modeling parameters which govern the outcomes of the system is very challenging. Sensitivity analysis plays a vital role in quantifying the impact of modeling parameters in massively interacting systems, including large complex ABM. The high computational cost of executing simulations impedes running experiments with exhaustive parameter settings. Existing techniques of analyzing such a complex system typically focus on local sensitivity analysis, i.e. one parameter at a time, or a close “neighborhood” of particular parameter settings. However, such methods are not adequate to measure the uncertainty and sensitivity of parameters accurately because they overlook the global impacts of parameters on the system. In this article, we develop novel experimental design and analysis techniques to perform both global and local sensitivity analysis of large-scale ABMs. The proposed method can efficiently identify the most significant parameters and quantify their contributions to outcomes of the system. We demonstrate the proposed methodology for ENteric Immune SImulator (ENISI), a large-scale ABM environment, using a computational model of immune responses to Helicobacter pylori colonization of the gastric mucosa. PMID:26327290

Sensitivity Analysis of an ENteric Immunity SImulator (ENISI)-Based Model of Immune Responses to Helicobacter pylori Infection.

PubMed

Alam, Maksudul; Deng, Xinwei; Philipson, Casandra; Bassaganya-Riera, Josep; Bisset, Keith; Carbo, Adria; Eubank, Stephen; Hontecillas, Raquel; Hoops, Stefan; Mei, Yongguo; Abedi, Vida; Marathe, Madhav

2015-01-01

Agent-based models (ABM) are widely used to study immune systems, providing a procedural and interactive view of the underlying system. The interaction of components and the behavior of individual objects is described procedurally as a function of the internal states and the local interactions, which are often stochastic in nature. Such models typically have complex structures and consist of a large number of modeling parameters. Determining the key modeling parameters which govern the outcomes of the system is very challenging. Sensitivity analysis plays a vital role in quantifying the impact of modeling parameters in massively interacting systems, including large complex ABM. The high computational cost of executing simulations impedes running experiments with exhaustive parameter settings. Existing techniques of analyzing such a complex system typically focus on local sensitivity analysis, i.e. one parameter at a time, or a close "neighborhood" of particular parameter settings. However, such methods are not adequate to measure the uncertainty and sensitivity of parameters accurately because they overlook the global impacts of parameters on the system. In this article, we develop novel experimental design and analysis techniques to perform both global and local sensitivity analysis of large-scale ABMs. The proposed method can efficiently identify the most significant parameters and quantify their contributions to outcomes of the system. We demonstrate the proposed methodology for ENteric Immune SImulator (ENISI), a large-scale ABM environment, using a computational model of immune responses to Helicobacter pylori colonization of the gastric mucosa.

The design and implementation of the immune epitope database and analysis resource

PubMed Central

Peters, Bjoern; Sidney, John; Bourne, Phil; Bui, Huynh-Hoa; Buus, Soeren; Doh, Grace; Fleri, Ward; Kronenberg, Mitch; Kubo, Ralph; Lund, Ole; Nemazee, David; Ponomarenko, Julia V.; Sathiamurthy, Muthu; Schoenberger, Stephen P.; Stewart, Scott; Surko, Pamela; Way, Scott; Wilson, Steve; Sette, Alessandro

2016-01-01

Epitopes are defined as parts of antigens interacting with receptors of the immune system. Knowledge about their intrinsic structure and how they affect the immune response is required to continue development of techniques that detect, monitor, and fight diseases. Their scientific importance is reflected in the vast amount of epitope-related information gathered, ranging from interactions between epitopes and major histocompatibility complex molecules determined by X-ray crystallography to clinical studies analyzing correlates of protection for epitope based vaccines. Our goal is to provide a central resource capable of capturing this information, allowing users to access and connect realms of knowledge that are currently separated and difficult to access. Here, we portray a new initiative, “The Immune Epitope Database and Analysis Resource.” We describe how we plan to capture, structure, and store this information, what query interfaces we will make available to the public, and what additional predictive and analytical tools we will provide. PMID:15895191

Integrated Omics and Computational Glycobiology Reveal Structural Basis for Influenza A Virus Glycan Microheterogeneity and Host Interactions.

PubMed

Khatri, Kshitij; Klein, Joshua A; White, Mitchell R; Grant, Oliver C; Leymarie, Nancy; Woods, Robert J; Hartshorn, Kevan L; Zaia, Joseph

2016-06-01

Despite sustained biomedical research effort, influenza A virus remains an imminent threat to the world population and a major healthcare burden. The challenge in developing vaccines against influenza is the ability of the virus to mutate rapidly in response to selective immune pressure. Hemagglutinin is the predominant surface glycoprotein and the primary determinant of antigenicity, virulence and zoonotic potential. Mutations leading to changes in the number of HA glycosylation sites are often reported. Such genetic sequencing studies predict at best the disruption or creation of sequons for N-linked glycosylation; they do not reflect actual phenotypic changes in HA structure. Therefore, combined analysis of glycan micro and macro-heterogeneity and bioassays will better define the relationships among glycosylation, viral bioactivity and evolution. We present a study that integrates proteomics, glycomics and glycoproteomics of HA before and after adaptation to innate immune system pressure. We combined this information with glycan array and immune lectin binding data to correlate the phenotypic changes with biological activity. Underprocessed glycoforms predominated at the glycosylation sites found to be involved in viral evolution in response to selection pressures and interactions with innate immune-lectins. To understand the structural basis for site-specific glycan microheterogeneity at these sites, we performed structural modeling and molecular dynamics simulations. We observed that the presence of immature, high-mannose type glycans at a particular site correlated with reduced accessibility to glycan remodeling enzymes. Further, the high mannose glycans at sites implicated in immune lectin recognition were predicted to be capable of forming trimeric interactions with the immune-lectin surfactant protein-D. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pattern recognition receptor immunomodulation of innate immunity as a strategy to limit the impact of influenza virus.

PubMed

Pizzolla, Angela; Smith, Jeffery M; Brooks, Andrew G; Reading, Patrick C

2017-04-01

Influenza remains a major global health issue and the effectiveness of current vaccines and antiviral drugs is limited by the continual evolution of influenza viruses. Therefore, identifying novel prophylactic or therapeutic treatments that induce appropriate innate immune responses to protect against influenza infection would represent an important advance in efforts to limit the impact of influenza. Cellular pattern recognition receptors (PRRs) recognize conserved structures expressed by pathogens to trigger intracellular signaling cascades, promoting expression of proinflammatory molecules and innate immunity. Therefore, a number of approaches have been developed to target specific PRRs in an effort to stimulate innate immunity and reduce disease in a variety of settings, including during influenza infections. Herein, we discuss progress in immunomodulation strategies designed to target cell-associated PRRs of the innate immune system, thereby, modifying innate responses to IAV infection and/or augmenting immune responses to influenza vaccines. © Society for Leukocyte Biology.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Kemin; Johnson, Parker M.; Stols, Lucy

Contact-dependent growth inhibition (CDI) is an important mechanism of intercellular competition between neighboring Gram-negative bacteria. CDI systems encode large surface-exposed CdiA effector proteins that carry a variety of C-terminal toxin domains (CdiA-CTs). All CDI +bacteria also produce CdiI immunity proteins that specifically bind to the cognate CdiA-CT and neutralize its toxin activity to prevent auto-inhibition. Here, the X-ray crystal structure of a CdiI immunity protein fromNeisseria meningitidisMC58 is presented at 1.45 Å resolution. The CdiI protein has structural homology to the Whirly family of RNA-binding proteins, but appears to lack the characteristic nucleic acid-binding motif of this family. Sequence homologymore » suggests that the cognate CdiA-CT is related to the eukaryotic EndoU family of RNA-processing enzymes. A homology model is presented of the CdiA-CT based on the structure of the XendoU nuclease fromXenopus laevis. Molecular-docking simulations predict that the CdiA-CT toxin active site is occluded upon binding to the CdiI immunity protein. Together, these observations suggest that the immunity protein neutralizes toxin activity by preventing access to RNA substrates.« less

Human NOD2 Recognizes Structurally Unique Muramyl Dipeptides from Mycobacterium leprae.

PubMed

Schenk, Mirjam; Mahapatra, Sebabrata; Le, Phuonganh; Kim, Hee Jin; Choi, Aaron W; Brennan, Patrick J; Belisle, John T; Modlin, Robert L

2016-09-01

The innate immune system recognizes microbial pathogens via pattern recognition receptors. One such receptor, NOD2, via recognition of muramyl dipeptide (MDP), triggers a distinct network of innate immune responses, including the production of interleukin-32 (IL-32), which leads to the differentiation of monocytes into dendritic cells (DC). NOD2 has been implicated in the pathogenesis of human leprosy, yet it is not clear whether Mycobacterium leprae, which has a distinct MDP structure, can activate this pathway. We investigated the effect of MDP structure on the innate immune response, finding that infection of monocytes with M. leprae induces IL-32 and DC differentiation in a NOD2-dependent manner. The presence of the proximal l-Ala instead of Gly in the common configuration of the peptide side chain of M. leprae did not affect recognition by NOD2 or cytokine production. Furthermore, amidation of the d-Glu residue did not alter NOD2 activation. These data provide experimental evidence that NOD2 recognizes naturally occurring structural variants of MDP. Copyright © 2016 Schenk et al.

A qualitative analysis of immunization programs with sustained high coverage, 2000-2005.

PubMed

Kennedy, Allison; Groom, Holly; Evans, Victoria; Fasano, Nancy

2010-01-01

Despite record-high immunization coverage nationally, there is considerable variation across state and local immunization programs, which are responsible for the implementation of vaccine recommendations in their jurisdictions. The objectives of this study were to describe activities of state and local immunization programs that sustained high coverage levels across several years and to identify common themes and practical examples for sustaining childhood vaccination coverage rates that could be applied elsewhere. We conducted 95 semi-structured key informant interviews with internal staff members and external partners at the 10 immunization programs with the highest sustained childhood immunization coverage from 2000 to 2005, as measured by the National Immunization Survey. Interview transcripts were analyzed qualitatively using a general inductive approach. Common themes across the 10 programs included maintaining a strong program infrastructure, using available data to drive planning and decision making, a commitment to building and sustaining relationships, and a focus on education and communication. Given the challenges of an increasingly complex immunization system, the lessons learned from these programs may help inform others who are working to improve childhood immunization delivery and coverage in their own programs.

Recent findings on the structure and function of teleost IgT

PubMed Central

Zhang, Yong-An; Salinas, Irene; Sunyer, J. Oriol

2011-01-01

As key effector molecules of jawed vertebrate’s adaptive immune system, immunoglobulins are produced by B lymphocytes, either as a secretory form (antibody) or as a membrane form (B cell receptor). Until recently, teleost fish B cells were thought to express only two classes of immunoglobulins, IgM and IgD. In addition, IgM in these species was thought to be the only immunoglobulin isotype responding to pathogens both in systemic or mucosal compartments. However, the unexpected discovery of IgT, a new teleost immunoglobulin unearthed in 2005, has provided for new opportunities to analyze further roles of teleost immunoglobulins in these two physiologically distinct compartments. The smoke about the potential function of IgT has cleared recently with the finding that this immunoglobulin appears to be specialized in gut mucosal immunity. Significantly, the new capability of measuring not only IgM but also IgT responses will greatly facilitate the evaluation and understanding of fish immune responses as well as the protective effects of fish vaccines. The purpose of this review is to summarize the molecular characterization of new IgT orthologs and subtypes in teleosts, as well as to describe the new findings concerning the protein structure of IgT, the B cells producing it, and its role in mucosal immunity. PMID:21466854

Structure and mechanism of a molecular rheostat, an RNA thermometer that modulates immune evasion by Neisseria meningitidis

PubMed Central

Barnwal, Ravi Pratap; Loh, Edmund; Godin, Katherine S.; Yip, Jordan; Lavender, Hayley; Tang, Christoph M.; Varani, Gabriele

2016-01-01

Neisseria meningitidis causes bacterial meningitis and septicemia. It evades the host complement system by upregulating expression of immune evasion factors in response to changes in temperature. RNA thermometers within mRNAs control expression of bacterial immune evasion factors, including CssA, in the 5′-untranslated region of the operon for capsule biosynthesis. We dissect the molecular mechanisms of thermoregulation and report the structure of the CssA thermometer. We show that the RNA thermometer acts as a rheostat, whose stability is optimized to respond in a small temperature range around 37°C as occur within the upper airways during infection. Small increases in temperature gradually open up the structure to allow progressively increased access to the ribosome binding site. Even small changes in stability induced by mutations of imperfect base pairs, as in naturally occurring polymorphisms, shift the thermometer response outside of the desired temperature range, suggesting that its activity could be modulated by pharmacological intervention. PMID:27369378

Structure of the Toll-Spatzle complex, a molecular hub in Drosophila development and innate immunity.

PubMed

Parthier, Christoph; Stelter, Marco; Ursel, Christian; Fandrich, Uwe; Lilie, Hauke; Breithaupt, Constanze; Stubbs, Milton T

2014-04-29

Drosophila Toll receptors are involved in embryonic development and the immune response of adult flies. In both processes, the only known Toll receptor ligand is the human nerve growth factor-like cystine knot protein Spätzle. Here we present the crystal structure of a 1:1 (nonsignaling) complex of the full-length Toll receptor ectodomain (ECD) with the Spätzle cystine knot domain dimer. The ECD is divided into two leucine-rich repeat (LRR) domains, each of which is capped by cysteine-rich domains. Spätzle binds to the concave surface of the membrane-distal LRR domain, in contrast to the flanking ligand interactions observed for mammalian Toll-like receptors, with asymmetric contributions from each Spätzle protomer. The structure allows rationalization of existing genetic and biochemical data and provides a framework for targeting the immune systems of insects of economic importance, as well as a variety of invertebrate disease vectors.

siRNA and innate immunity.

PubMed

Robbins, Marjorie; Judge, Adam; MacLachlan, Ian

2009-06-01

Canonical small interfering RNA (siRNA) duplexes are potent activators of the mammalian innate immune system. The induction of innate immunity by siRNA is dependent on siRNA structure and sequence, method of delivery, and cell type. Synthetic siRNA in delivery vehicles that facilitate cellular uptake can induce high levels of inflammatory cytokines and interferons after systemic administration in mammals and in primary human blood cell cultures. This activation is predominantly mediated by immune cells, normally via a Toll-like receptor (TLR) pathway. The siRNA sequence dependency of these pathways varies with the type and location of the TLR involved. Alternatively nonimmune cell activation may also occur, typically resulting from siRNA interaction with cytoplasmic RNA sensors such as RIG1. As immune activation by siRNA-based drugs represents an undesirable side effect due to the considerable toxicities associated with excessive cytokine release in humans, understanding and abrogating this activity will be a critical component in the development of safe and effective therapeutics. This review describes the intracellular mechanisms of innate immune activation by siRNA, the design of appropriate sequences and chemical modification approaches, and suitable experimental methods for studying their effects, with a view toward reducing siRNA-mediated off-target effects.

Plasmodium evasion of mosquito immunity and global malaria transmission: The lock-and-key theory.

PubMed

Molina-Cruz, Alvaro; Canepa, Gaspar E; Kamath, Nitin; Pavlovic, Noelle V; Mu, Jianbing; Ramphul, Urvashi N; Ramirez, Jose Luis; Barillas-Mury, Carolina

2015-12-08

Plasmodium falciparum malaria originated in Africa and became global as humans migrated to other continents. During this journey, parasites encountered new mosquito species, some of them evolutionarily distant from African vectors. We have previously shown that the Pfs47 protein allows the parasite to evade the mosquito immune system of Anopheles gambiae mosquitoes. Here, we investigated the role of Pfs47-mediated immune evasion in the adaptation of P. falciparum to evolutionarily distant mosquito species. We found that P. falciparum isolates from Africa, Asia, or the Americas have low compatibility to malaria vectors from a different continent, an effect that is mediated by the mosquito immune system. We identified 42 different haplotypes of Pfs47 that have a strong geographic population structure and much lower haplotype diversity outside Africa. Replacement of the Pfs47 haplotypes in a P. falciparum isolate is sufficient to make it compatible to a different mosquito species. Those parasites that express a Pfs47 haplotype compatible with a given vector evade antiplasmodial immunity and survive. We propose that Pfs47-mediated immune evasion has been critical for the globalization of P. falciparum malaria as parasites adapted to new vector species. Our findings predict that this ongoing selective force by the mosquito immune system could influence the dispersal of Plasmodium genetic traits and point to Pfs47 as a potential target to block malaria transmission. A new model, the "lock-and-key theory" of P. falciparum globalization, is proposed, and its implications are discussed.

Molecular architecture of the fruit fly's airway epithelial immune system.

PubMed

Wagner, Christina; Isermann, Kerstin; Fehrenbach, Heinz; Roeder, Thomas

2008-09-29

Airway epithelial cells not only constitute a physical barrier, but also the first line of defence against airborne pathogens. At the same time, they are constantly exposed to reactive oxygen species. Therefore, airway epithelia cells have to possess a sophisticated innate immune system and a molecular armamentarium to detoxify reactive oxygen species. It has become apparent that deregulation of epithelial innate immunity is a major reason for the development of chronic inflammatory lung diseases. To elucidate the molecular architecture of the innate immune system of airway epithelial cells, we choose the fruit fly Drosophila melanogaster as a model, because it has the simplest type of airways, consisting of epithelial cells only. Elucidating the structure of the innate immune system of this "airway epithelial cell culture" might enable us to understand why deregulatory processes in innate immune signalling cascades lead to long lasting inflammatory events. All airway epithelial cells of the fruit fly are able to launch an immune response. They contain only one functional signal transduction pathway that converges onto NF-kappaB factors, namely the IMD-pathway, which is homologous to the TNF-alpha receptor pathway. Although vital parts of the Toll-pathway are missing, dorsal and dif, the NF-kappaB factors dedicated to this signalling system, are present. Other pathways involved in immune regulation, such as the JNK- and the JAK/STAT-pathway, are completely functional in these cells. In addition, most peptidoglycan recognition proteins, representing the almost complete collection of pattern recognition receptors, are part of the epithelial cells equipment. Potential effector molecules are different antimicrobial peptides and lysozymes, but also transferrin that can inhibit bacterial growth through iron-depletion. Reactive oxygen species can be inactivated through the almost complete armamentarium of enzymatic antioxidants that has the fly to its disposal. The innate immune system of the fly's airway epithelium has a very peculiar organization. A great variety of pattern recognition receptors as well as of potential effector molecules are conspicuous, whereas signalling presumably occurs through a single NF-kappaB activating pathway. This architecture will allow reacting if confronted with different bacterial or fungal elicitors by activation of a multitude of effectors.

Physical mode of bacteria and virus coevolution

NASA Astrophysics Data System (ADS)

Han, Pu; Niestemski, Liang; Deem, Michael

2013-03-01

Single-cell hosts such as bacteria or archaea possess an adaptive, heritable immune system that protects them from viral invasion. This system, known as the CRISPR-Cas system, allows the host to recognize and incorporate short foreign DNA or RNA sequences from viruses or plasmids. The sequences form what are called ``spacers'' in the CRISPR. Spacers in the CRISPR loci provide a record of the host and predator coevolution history. We develop a physical model to study the dynamics of this coevolution due to immune pressure. Hosts and viruses reproduce, die, and evolve due to viral infection pressure, host immune pressure, and mutation. We will discuss the differing effects of point mutation and recombination on CRISPR evolution. We will also discuss the effect of different spacer deletion mechanisms. We will describe population structure of hosts and viruses, how spacer diversity depends on position within CRISPR, and match of the CRISPR spacers to the virus population.

Immune responses to invasive aspergillosis: new understanding and therapeutic opportunities

PubMed Central

Hohl, Tobias M.

2017-01-01

Purpose of review Invasive aspergillosis is a worldwide disease that primarily affects immune-compromised patients, agricultural workers with corneal abrasions, individuals with structural lung disease, and patients with primary immune deficiency. The critical function of the immune system is to prevent the germination of airborne conidia into tissue-invasive hyphae. This review covers recent advances that shape our understanding of anti-Aspergillus immunity at the molecular and cellular level. Recent findings Host defense against conidia and hyphae occurs via distinct molecular mechanisms that involve intracellular and extracellular killing pathways, as well as cooperation between different myeloid cell subsets. The strength and efficacy of the host response is shaped by the tissue microenvironment. In preclinical models of disease, host immune augmentation strategies have yielded benefits, yet translating these insights into therapeutic strategies in humans remains challenging. Summary Although advances in early diagnostic strategies and in antifungal drugs have ameliorated clinical outcomes of invasive aspergillosis, further improvements depend on gaining deeper insight into and translating advances in anti-Aspergillus immunity. PMID:28509673

Nanoparticle Vaccines Adopting Virus-like Features for Enhanced Immune Potentiation

PubMed Central

Chattopadhyay, Saborni; Chen, Jui-Yi; Chen, Hui-Wen; Hu, Che-Ming Jack

2017-01-01

Synthetic nanoparticles play an increasingly significant role in vaccine design and development as many nanoparticle vaccines show improved safety and efficacy over conventional formulations. These nanoformulations are structurally similar to viruses, which are nanoscale pathogenic organisms that have served as a key selective pressure driving the evolution of our immune system. As a result, mechanisms behind the benefits of nanoparticle vaccines can often find analogue to the interaction dynamics between the immune system and viruses. This review covers the advances in vaccine nanotechnology with a perspective on the advantages of virus mimicry towards immune potentiation. It provides an overview to the different types of nanomaterials utilized for nanoparticle vaccine development, including functionalization strategies that bestow nanoparticles with virus-like features. As understanding of human immunity and vaccine mechanisms continue to evolve, recognizing the fundamental semblance between synthetic nanoparticles and viruses may offer an explanation for the superiority of nanoparticle vaccines over conventional vaccines and may spur new design rationales for future vaccine research. These nanoformulations are poised to provide solutions towards pressing and emerging human diseases. PMID:29071191

Mechanisms for Cell-to-Cell Transmission of HIV-1

PubMed Central

Bracq, Lucie; Xie, Maorong; Benichou, Serge; Bouchet, Jérôme

2018-01-01

While HIV-1 infection of target cells with cell-free viral particles has been largely documented, intercellular transmission through direct cell-to-cell contact may be a predominant mode of propagation in host. To spread, HIV-1 infects cells of the immune system and takes advantage of their specific particularities and functions. Subversion of intercellular communication allows to improve HIV-1 replication through a multiplicity of intercellular structures and membrane protrusions, like tunneling nanotubes, filopodia, or lamellipodia-like structures involved in the formation of the virological synapse. Other features of immune cells, like the immunological synapse or the phagocytosis of infected cells are hijacked by HIV-1 and used as gateways to infect target cells. Finally, HIV-1 reuses its fusogenic capacity to provoke fusion between infected donor cells and target cells, and to form infected syncytia with high capacity of viral production and improved capacities of motility or survival. All these modes of cell-to-cell transfer are now considered as viral mechanisms to escape immune system and antiretroviral therapies, and could be involved in the establishment of persistent virus reservoirs in different host tissues. PMID:29515578

Damage detection based on acceleration data using artificial immune system

NASA Astrophysics Data System (ADS)

Chartier, Sandra; Mita, Akira

2009-03-01

Nowadays, Structural Health Monitoring (SHM) is essential in order to prevent damages occurrence in civil structures. This is a particularly important issue as the number of aged structures is increasing. Damage detection algorithms are often based on changes in the modal properties like natural frequencies, modal shapes and modal damping. In this paper, damage detection is completed by using Artificial Immune System (AIS) theory directly on acceleration data. Inspired from the biological immune system, AIS is composed of several models like negative selection which has a great potential for this study. The negative selection process relies on the fact that T-cells, after their maturation, are sensitive to non self cells and can not detect self cells. Acceleration data were provided by using the numerical model of a 3-story frame structure. Damages were introduced, at particular times, by reduction of story's stiffness. Based on these acceleration data, undamaged data (equivalent to self data) and damaged data (equivalent to non self data) can be obtained and represented in the Hamming shape-space with a binary representation. From the undamaged encoded data, detectors (equivalent to T-cells) are derived and are able to detect damaged encoded data really efficiently by using the rcontiguous bits matching rule. Indeed, more than 95% of detection can be reached when efficient combinations of parameters are used. According to the number of detected data, the localization of damages can even be determined by using the differences between story's relative accelerations. Thus, the difference which presents the highest detection rate, generally up to 89%, is directly linked to the location of damage.

Immunology of whales and dolphins.

PubMed

Beineke, Andreas; Siebert, Ursula; Wohlsein, Peter; Baumgärtner, Wolfgang

2010-02-15

The increasing disease susceptibility in different whale and dolphin populations has led to speculation about a possible negative influence of environmental contaminants on the immune system and therefore on the health status of marine mammals. Despite current efforts in the immunology of marine mammals several aspects of immune functions in aquatic mammals remain unknown. However, assays for evaluating cellular immune responses, such as lymphocyte proliferation, respiratory burst as well as phagocytic and cytotoxic activity of leukocytes and humoral immune responses have been established for different cetacean species. Additionally, immunological and molecular techniques enable the detection and quantification of pro- and anti-inflammatory cytokines in lymphoid cells during inflammation or immune responses, respectively. Different T and B cell subsets as well as antigen-presenting cells can be detected by flow cytometry and immunohistochemistry. Despite great homologies between marine and terrestrial mammal lymphoid organs, some unique anatomical structures, particularly the complex lymphoepithelial laryngeal glands in cetaceans represent an adaptation to the marine environment. Additionally, physiological changes, such as age-related thymic atrophy and cystic degeneration of the "anal tonsil" of whales have to be taken into account when investigating these lymphoid structures. Systemic morbillivirus infections lead to fatalities in cetaceans associated with generalized lymphoid depletion. Similarly, chronic diseases and starvation are associated with a loss of functional lymphoid cells and decreased resistance against opportunistic infections. There is growing evidence for an immunotoxic effect of different environmental contaminants in whales and dolphins, as demonstrated in field studies. Furthermore, immunomodulatory properties of different persistent xenobiotics have been confirmed in cetacean lymphoid cells in vitro as well as in animal models in vivo. However, species-specific differences of the immune system and detoxification of xenobiotics between cetaceans and laboratory rodents have to be considered when interpreting these toxicological data for risk assessment in whales and dolphins. Copyright 2009 Elsevier B.V. All rights reserved.

Chitin and Its Effects on Inflammatory and Immune Responses.

PubMed

Elieh Ali Komi, Daniel; Sharma, Lokesh; Dela Cruz, Charles S

2018-04-01

Chitin, a potential allergy-promoting pathogen-associated molecular pattern (PAMP), is a linear polymer composed of N-acetylglucosamine residues which are linked by β-(1,4)-glycosidic bonds. Mammalians are potential hosts for chitin-containing protozoa, fungi, arthropods, and nematodes; however, mammalians themselves do not synthetize chitin and thus it is considered as a potential target for recognition by mammalian immune system. Chitin is sensed primarily in the lungs or gut where it activates a variety of innate (eosinophils, macrophages) and adaptive immune cells (IL-4/IL-13 expressing T helper type-2 lymphocytes). Chitin induces cytokine production, leukocyte recruitment, and alternative macrophage activation. Intranasal or intraperitoneal administration of chitin (varying in size, degree of acetylation and purity) to mice has been applied as a routine approach to investigate chitin's priming effects on innate and adaptive immunity. Structural chitin present in microorganisms is actively degraded by host true chitinases, including acidic mammalian chitinases and chitotriosidase into smaller fragments that can be sensed by mammalian receptors such as FIBCD1, NKR-P1, and RegIIIc. Immune recognition of chitin also involves pattern recognition receptors, mainly via TLR-2 and Dectin-1, to activate immune cells to induce cytokine production and creation of an immune network that results in inflammatory and allergic responses. In this review, we will focus on various immunological aspects of the interaction between chitin and host immune system such as sensing, interactions with immune cells, chitinases as chitin degrading enzymes, and immunologic applications of chitin.

Changing expression of vertebrate immunity genes in an anthropogenic environment: a controlled experiment.

PubMed

Hablützel, Pascal I; Brown, Martha; Friberg, Ida M; Jackson, Joseph A

2016-09-01

The effect of anthropogenic environments on the function of the vertebrate immune system is a problem of general importance. For example, it relates to the increasing rates of immunologically-based disease in modern human populations and to the desirability of identifying optimal immune function in domesticated animals. Despite this importance, our present understanding is compromised by a deficit of experimental studies that make adequately matched comparisons between wild and captive vertebrates. We transferred post-larval fishes (three-spined sticklebacks), collected in the wild, to an anthropogenic (captive) environment. We then monitored, over 11 months, how the systemic expression of immunity genes changed in comparison to cohort-matched wild individuals in the originator population (total n = 299). We found that a range of innate (lyz, defbl2, il1r-like, tbk1) and adaptive (cd8a, igmh) immunity genes were up-regulated in captivity, accompanied by an increase in expression of the antioxidant enzyme, gpx4a. For some genes previously known to show seasonality in the wild, this appeared to be reduced in captive fishes. Captive fishes tended to express immunity genes, including igzh, foxp3b, lyz, defbl2, and il1r-like, more variably. Furthermore, although gene co-expression patterns (analyzed through gene-by-gene correlations and mutual information theory based networks) shared common structure in wild and captive fishes, there was also significant divergence. For one gene in particular, defbl2, high expression was associated with adverse health outcomes in captive fishes. Taken together, these results demonstrate widespread regulatory changes in the immune system in captive populations, and that the expression of immunity genes is more constrained in the wild. An increase in constitutive systemic immune activity, such as we observed here, may alter the risk of immunopathology and contribute to variance in health in vertebrate populations exposed to anthropogenic environments.

Phospholipase C-β in immune cells.

PubMed

Kawakami, Toshiaki; Xiao, Wenbin

2013-09-01

Great progress has recently been made in structural and functional research of phospholipase C (PLC)-β. We now understand how PLC-β isoforms (β1-β4) are activated by GTP-bound Gαq downstream of G protein-coupled receptors. Numerous studies indicate that PLC-βs participate in the differentiation and activation of immune cells that control both the innate and adaptive immune systems. The PLC-β3 isoform also interplays with tyrosine kinase-based signaling pathways, to inhibit Stat5 activation by recruiting the protein-tyrosine phosphatase SHP-1, with which PLC-β3 and Stat5 form a multi-molecular signaling platform, named SPS complex. The SPS complex has important regulatory roles in tumorigenesis and immune cell activation. Copyright © 2013 Elsevier Ltd. All rights reserved.

Phospholipase C-β in Immune Cells

PubMed Central

Kawakami, Toshiaki; Xiao, Wenbin

2013-01-01

Great progress has recently been made in structural and functional research of phospholipase C (PLC)-β. We now understand how PLC-β isoforms (β1-β4) are activated by GTP-bound Gαq downstream of G protein-coupled receptors. Numerous studies indicate that PLC-βs participate in the differentiation and activation of immune cells that control both the innate and adaptive immune systems. The PLC-β3 isoform also interplays with tyrosine kinase-based signaling pathways, to inhibit Stat5 activation by recruiting the protein-tyrosine phosphatase SHP-1, with which PLC-β3 and Stat5 form a multi-molecular signaling platform, named SPS complex. The SPS complex has important regulatory roles in tumorigenesis and immune cell activation. PMID:23981313

EpitopeViewer: a Java application for the visualization and analysis of immune epitopes in the Immune Epitope Database and Analysis Resource (IEDB).

PubMed

Beaver, John E; Bourne, Philip E; Ponomarenko, Julia V

2007-02-21

Structural information about epitopes, particularly the three-dimensional (3D) structures of antigens in complex with immune receptors, presents a valuable source of data for immunology. This information is available in the Protein Data Bank (PDB) and provided in curated form by the Immune Epitope Database and Analysis Resource (IEDB). With continued growth in these data and the importance in understanding molecular level interactions of immunological interest there is a need for new specialized molecular visualization and analysis tools. The EpitopeViewer is a platform-independent Java application for the visualization of the three-dimensional structure and sequence of epitopes and analyses of their interactions with antigen-specific receptors of the immune system (antibodies, T cell receptors and MHC molecules). The viewer renders both 3D views and two-dimensional plots of intermolecular interactions between the antigen and receptor(s) by reading curated data from the IEDB and/or calculated on-the-fly from atom coordinates from the PDB. The 3D views and associated interactions can be saved for future use and publication. The EpitopeViewer can be accessed from the IEDB Web site http://www.immuneepitope.org through the quick link 'Browse Records by 3D Structure.' The EpitopeViewer is designed and been tested for use by immunologists with little or no training in molecular graphics. The EpitopeViewer can be launched from most popular Web browsers without user intervention. A Java Runtime Environment (RJE) 1.4.2 or higher is required.

Osteoimmunology: the study of the relationship between the immune system and bone tissue.

PubMed

Arboleya, Luis; Castañeda, Santos

2013-01-01

Bone tissue is a highly regulated structure, which plays an essential role in various physiological functions. Through autocrine and paracrine mechanisms, bone tissue is involved in hematopoiesis, influencing the fate of hematopoietic stem cells. There are a number of molecules shared by bone cells and immune system cells indicating that there are multiple connections between the immune system and bone tissue. In order to pool all the knowledge concerning both systems, a new discipline known under the term «osteoimmunology» has been developed. Their progress in recent years has been exponential and allowed us to connect and increase our knowledge in areas not seemingly related such as rheumatoid erosion, postmenopausal osteoporosis, bone metastases or periodontal disease. In this review, we have tried to summarize the most important advances that have occurred in the last decade, especially in those areas of interest related to rheumatology. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Cryo-EM Structures Reveal Mechanism and Inhibition of DNA Targeting by a CRISPR-Cas Surveillance Complex.

PubMed

Guo, Tai Wei; Bartesaghi, Alberto; Yang, Hui; Falconieri, Veronica; Rao, Prashant; Merk, Alan; Eng, Edward T; Raczkowski, Ashleigh M; Fox, Tara; Earl, Lesley A; Patel, Dinshaw J; Subramaniam, Sriram

2017-10-05

Prokaryotic cells possess CRISPR-mediated adaptive immune systems that protect them from foreign genetic elements, such as invading viruses. A central element of this immune system is an RNA-guided surveillance complex capable of targeting non-self DNA or RNA for degradation in a sequence- and site-specific manner analogous to RNA interference. Although the complexes display considerable diversity in their composition and architecture, many basic mechanisms underlying target recognition and cleavage are highly conserved. Using cryoelectron microscopy (cryo-EM), we show that the binding of target double-stranded DNA (dsDNA) to a type I-F CRISPR system yersinia (Csy) surveillance complex leads to large quaternary and tertiary structural changes in the complex that are likely necessary in the pathway leading to target dsDNA degradation by a trans-acting helicase-nuclease. Comparison of the structure of the surveillance complex before and after dsDNA binding, or in complex with three virally encoded anti-CRISPR suppressors that inhibit dsDNA binding, reveals mechanistic details underlying target recognition and inhibition. Published by Elsevier Inc.

Review of S100A9 Biology and its Role in Cancer

PubMed Central

Markowitz, Joseph; Carson, William E.

2013-01-01

S100A9 is a calcium binding protein with multiple ligands and post-translation modifications that is involved in inflammatory events and the initial development of the cancer cell through to the development of metastatic disease. This review has a threefold purpose: 1) describe S100A9 structural elements important for its biological activity, 2) describe S100A9 biology in the context of the immune system, and 3) illustrate the role of S100A9 in the development of malignancy via interactions with the immune system and other cellular processes. PMID:23123827

Potential immunotoxic effects of trichloroethylene-induced IV allergic reaction in renal impairment

PubMed Central

Yu, Jun-Feng; Feng, Yan-Yan

2017-01-01

Trichloroethylene (TCE) is known to induce allergic contact dermatitis and subsequent occupational medicamentosa-like dermatitis (OMLD) with multi-system injuries, including liver, kidney, and skin injuries. However, the mechanisms underlying immune system dysfunction that result in organ injury have not yet been clearly elucidated. In the present study, we measured the levels of secreted cytokines by effect or T cells in TCE-treated guinea pigs to better understand the contribution of allergic disorders in renal injuries. We immunized guinea pigs with trichloroethylene using the Guinea Pig Maximization Test (GPMT) and scored the inflammation on the guinea pigs’ skin. The kidney function and ultra-structural changes in the kidneys were detected using biochemical methods and electron microscopy. The deposition of cytokines was determined using immunohistochemistry. The sensitization rate was 63.16% in the TCE-sensitized groups. The electron microscopy results showed tubular epithelial cell mitochondrial swelling, vacuolar degeneration, and atrophy of the microvillus in the sensitized groups. A high degree of cytokine deposition was observed in the renal tubular proximal epithelial cells in the TCE-sensitized groups. As observed in this study, the variation in the level of immune system activation not only indicates that TCE can largely magnify the immune reaction but also suggests a potential role of immune dysfunction in renal impairment. PMID:28867961

Deciphering the Counterplay of Aspergillus fumigatus Infection and Host Inflammation by Evolutionary Games on Graphs

NASA Astrophysics Data System (ADS)

Pollmächer, Johannes; Timme, Sandra; Schuster, Stefan; Brakhage, Axel A.; Zipfel, Peter F.; Figge, Marc Thilo

2016-06-01

Microbial invaders are ubiquitously present and pose the constant risk of infections that are opposed by various defence mechanisms of the human immune system. A tight regulation of the immune response ensures clearance of microbial invaders and concomitantly limits host damage that is crucial for host viability. To investigate the counterplay of infection and inflammation, we simulated the invasion of the human-pathogenic fungus Aspergillus fumigatus in lung alveoli by evolutionary games on graphs. The layered structure of the innate immune system is represented by a sequence of games in the virtual model. We show that the inflammatory cascade of the immune response is essential for microbial clearance and that the inflammation level correlates with the infection-dose. At low infection-doses, corresponding to daily inhalation of conidia, the resident alveolar macrophages may be sufficient to clear infections, however, at higher infection-doses their primary task shifts towards recruitment of neutrophils to infection sites.

Deciphering the Counterplay of Aspergillus fumigatus Infection and Host Inflammation by Evolutionary Games on Graphs

PubMed Central

Pollmächer, Johannes; Timme, Sandra; Schuster, Stefan; Brakhage, Axel A.; Zipfel, Peter F.; Figge, Marc Thilo

2016-01-01

Microbial invaders are ubiquitously present and pose the constant risk of infections that are opposed by various defence mechanisms of the human immune system. A tight regulation of the immune response ensures clearance of microbial invaders and concomitantly limits host damage that is crucial for host viability. To investigate the counterplay of infection and inflammation, we simulated the invasion of the human-pathogenic fungus Aspergillus fumigatus in lung alveoli by evolutionary games on graphs. The layered structure of the innate immune system is represented by a sequence of games in the virtual model. We show that the inflammatory cascade of the immune response is essential for microbial clearance and that the inflammation level correlates with the infection-dose. At low infection-doses, corresponding to daily inhalation of conidia, the resident alveolar macrophages may be sufficient to clear infections, however, at higher infection-doses their primary task shifts towards recruitment of neutrophils to infection sites. PMID:27291424

Metabolic labelling of the carbohydrate core in bacterial peptidoglycan and its applications

PubMed Central

Liang, Hai; DeMeester, Kristen E.; Hou, Ching-Wen; Parent, Michelle A.; Caplan, Jeffrey L.; Grimes, Catherine L.

2017-01-01

Bacterial cells are surrounded by a polymer known as peptidoglycan (PG), which protects the cell from changes in osmotic pressure and small molecule insults. A component of this material, N-acetyl-muramic acid (NAM), serves as a core structural element for innate immune recognition of PG fragments. We report the synthesis of modifiable NAM carbohydrate derivatives and the installation of these building blocks into the backbone of Gram-positive and Gram-negative bacterial PG utilizing metabolic cell wall recycling and biosynthetic machineries. Whole cells are labelled via click chemistry and visualized using super-resolution microscopy, revealing higher resolution PG structural details and allowing the cell wall biosynthesis, as well as its destruction in immune cells, to be tracked. This study will assist in the future identification of mechanisms that the immune system uses to recognize bacteria, glean information about fundamental cell wall architecture and aid in the design of novel antibiotics. PMID:28425464

Structure and Function of Viral Deubiquitinating Enzymes.

PubMed

Bailey-Elkin, Ben A; Knaap, Robert C M; Kikkert, Marjolein; Mark, Brian L

2017-11-10

Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including innate and adaptive immune responses. Ubiquitin-mediated control over these processes can be reversed by cellular deubiquitinating enzymes (DUBs), which remove ubiquitin from cellular targets and depolymerize polyubiquitin chains. The importance of protein ubiquitination to host immunity has been underscored by the discovery of viruses that encode proteases with deubiquitinating activity, many of which have been demonstrated to actively corrupt cellular ubiquitin-dependent processes to suppress innate antiviral responses and promote viral replication. DUBs have now been identified in diverse viral lineages, and their characterization is providing valuable insights into virus biology and the role of the ubiquitin system in host antiviral mechanisms. Here, we provide an overview of the structural biology of these fascinating viral enzymes and their role innate immune evasion and viral replication. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthetic RNAs Mimicking Structural Domains in the Foot-and-Mouth Disease Virus Genome Elicit a Broad Innate Immune Response in Porcine Cells Triggered by RIG-I and TLR Activation.

PubMed

Borrego, Belén; Rodríguez-Pulido, Miguel; Revilla, Concepción; Álvarez, Belén; Sobrino, Francisco; Domínguez, Javier; Sáiz, Margarita

2015-07-17

The innate immune system is the first line of defense against viral infections. Exploiting innate responses for antiviral, therapeutic and vaccine adjuvation strategies is being extensively explored. We have previously described, the ability of small in vitro RNA transcripts, mimicking the sequence and structure of different domains in the non-coding regions of the foot-and-mouth disease virus (FMDV) genome (ncRNAs), to trigger a potent and rapid innate immune response. These synthetic non-infectious molecules have proved to have a broad-range antiviral activity and to enhance the immunogenicity of an FMD inactivated vaccine in mice. Here, we have studied the involvement of pattern-recognition receptors (PRRs) in the ncRNA-induced innate response and analyzed the antiviral and cytokine profiles elicited in swine cultured cells, as well as peripheral blood mononuclear cells (PBMCs).

Crystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Hongmin; Astrof, Nathan S.; Liu, Jin-Huan

2009-09-15

Volatile anesthetics (VAs), such as isoflurane, induce a general anesthetic state by binding to specific targets (i.e., ion channels) in the central nervous system (CNS). Simultaneously, VAs modulate immune functions, possibly via direct interaction with alternative targets on leukocytes. One such target, the integrin lymphocyte function-associated antigen-1 (LFA-1), has been shown previously to be inhibited by isoflurane. A better understanding of the mechanism by which isoflurane alters protein function requires the detailed information about the drug-protein interaction at an atomic level. Here, we describe the crystal structure of the LFA-1 ligand-binding domain (I domain) in complex with isoflurane at 1.6more » {angstrom}. We discovered that isoflurane binds to an allosteric cavity previously implicated as critical for the transition of LFA-1 from the low- to the high-affinity state. The isoflurane binding site in the I domain involves an array of amphiphilic interactions, thereby resembling a 'common anesthetic binding motif' previously predicted for authentic VA binding sites. These results suggest that the allosteric modulation of protein function by isoflurane, as demonstrated for the integrin LFA-1, might represent a unified mechanism shared by the interactions of volatile anesthetics with targets in the CNS. Crystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems.« less

Structural Biology of Tumor Necrosis Factor Demonstrated for Undergraduates Instruction by Computer Simulation

ERIC Educational Resources Information Center

Roy, Urmi

2016-01-01

This work presents a three-dimensional (3D) modeling exercise for undergraduate students in chemistry and health sciences disciplines, focusing on a protein-group linked to immune system regulation. Specifically, the exercise involves molecular modeling and structural analysis of tumor necrosis factor (TNF) proteins, both wild type and mutant. The…

Guide-bound structures of an RNA-targeting A-cleaving CRISPR–Cas13a enzyme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knott, Gavin J.; East-Seletsky, Alexandra; Cofsky, Joshua C.

CRISPR adaptive immune systems protect bacteria from infections by deploying CRISPR RNA (crRNA)-guided enzymes to recognize and cut foreign nucleic acids. Type VI-A CRISPR–Cas systems include the Cas13a enzyme, an RNA-activated RNase capable of crRNA processing and single-stranded RNA degradation upon target-transcript binding. Here we present the 2.0-Å resolution crystal structure of a crRNA-bound Lachnospiraceae bacterium Cas13a (LbaCas13a), representing a recently discovered Cas13a enzyme subtype. This structure and accompanying biochemical experiments define the Cas13a catalytic residues that are directly responsible for crRNA maturation. In addition, the orientation of the foreign-derived target-RNA-specifying sequence in the protein interior explains the conformational gatingmore » of Cas13a nuclease activation. These results describe how Cas13a enzymes generate functional crRNAs and how catalytic activity is blocked before target-RNA recognition, with implications for both bacterial immunity and diagnostic applications.« less

Guide-bound structures of an RNA-targeting A-cleaving CRISPR–Cas13a enzyme

DOE PAGES

Knott, Gavin J.; East-Seletsky, Alexandra; Cofsky, Joshua C.; ...

2017-09-11

CRISPR adaptive immune systems protect bacteria from infections by deploying CRISPR RNA (crRNA)-guided enzymes to recognize and cut foreign nucleic acids. Type VI-A CRISPR–Cas systems include the Cas13a enzyme, an RNA-activated RNase capable of crRNA processing and single-stranded RNA degradation upon target-transcript binding. Here we present the 2.0-Å resolution crystal structure of a crRNA-bound Lachnospiraceae bacterium Cas13a (LbaCas13a), representing a recently discovered Cas13a enzyme subtype. This structure and accompanying biochemical experiments define the Cas13a catalytic residues that are directly responsible for crRNA maturation. In addition, the orientation of the foreign-derived target-RNA-specifying sequence in the protein interior explains the conformational gatingmore » of Cas13a nuclease activation. These results describe how Cas13a enzymes generate functional crRNAs and how catalytic activity is blocked before target-RNA recognition, with implications for both bacterial immunity and diagnostic applications.« less

Immune defense and host life history.

PubMed

Zuk, Marlene; Stoehr, Andrew M

2002-10-01

Recent interest has focused on immune response in an evolutionary context, with particular attention to disease resistance as a life-history trait, subject to trade-offs against other traits such as reproductive effort. Immune defense has several characteristics that complicate this approach, however; for example, because of the risk of autoimmunity, optimal immune defense is not necessarily maximum immune defense. Two important types of cost associated with immunity in the context of life history are resource costs, those related to the allocation of essential but limited resources, such as energy or nutrients, and option costs, those paid not in the currency of resources but in functional or structural components of the organism. Resource and option costs are likely to apply to different aspects of resistance. Recent investigations into possible trade-offs between reproductive effort, particularly sexual displays, and immunity have suggested interesting functional links between the two. Although all organisms balance the costs of immune defense against the requirements of reproduction, this balance works out differently for males than it does for females, creating sex differences in immune response that in turn are related to ecological factors such as the mating system. We conclude that immune response is indeed costly and that future work would do well to include invertebrates, which have sometimes been neglected in studies of the ecology of immune defense.

Whither vaccines?

PubMed

Rodrigues, Charlene M C; Pinto, Marta V; Sadarangani, Manish; Plotkin, Stanley A

2017-06-01

Currently used vaccines have had major effects on eliminating common infections, largely by duplicating the immune responses induced by natural infections. Now vaccinology faces more complex problems, such as waning antibody, immunosenescence, evasion of immunity by the pathogen, deviation of immunity by the microbiome, induction of inhibitory responses, and complexity of the antigens required for protection. Fortunately, vaccine development is now incorporating knowledge from immunology, structural biology, systems biology and synthetic chemistry to meet these challenges. In addition, international organisations are developing new funding and licensing pathways for vaccines aimed at pathogens with epidemic potential that emerge from tropical areas. © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Increase in DNA vaccine efficacy by virosome delivery and co-expression of a cytolytic protein.

PubMed

Gargett, Tessa; Grubor-Bauk, Branka; Miller, Darren; Garrod, Tamsin; Yu, Stanley; Wesselingh, Steve; Suhrbier, Andreas; Gowans, Eric J

2014-06-01

The potential of DNA vaccines has not been realised due to suboptimal delivery, poor antigen expression and the lack of localised inflammation, essential for antigen presentation and an effective immune response to the immunogen. Initially, we examined the delivery of a DNA vaccine encoding a model antigen, luciferase (LUC), to the respiratory tract of mice by encapsulation in a virosome. Virosomes that incorporated influenza virus haemagglutinin effectively delivered DNA to cells in the mouse respiratory tract and resulted in antigen expression and systemic and mucosal immune responses to the immunogen after an intranasal (IN) prime/intradermal (ID) boost regimen, whereas a multidose ID regimen only generated systemic immunity. We also examined systemic immune responses to LUC after ID vaccination with a DNA vaccine, which also encoded one of the several cytolytic or toxic proteins. Although the herpes simplex virus thymidine kinase, in the presence of the prodrug, ganciclovir, resulted in cell death, this failed to increase the humoral or cell-mediated immune responses. In contrast, the co-expression of LUC with the rotavirus non-structural protein 4 (NSP4) protein or a mutant form of mouse perforin, proteins which are directly cytolytic, resulted in increased LUC-specific humoral and cell-mediated immunity. On the other hand, co-expression of LUC with diphtheria toxin subunit A or overexpression of perforin or NSP4 resulted in a lower level of immunity. In summary, the efficacy of DNA vaccines can be improved by targeted IN delivery of DNA or by the induction of cell death in vaccine-targeted cells after ID delivery.

Porcine Reproductive and Respiratory Syndrome Virus (PRRSV): Pathogenesis and Interaction with the Immune System.

PubMed

Lunney, Joan K; Fang, Ying; Ladinig, Andrea; Chen, Nanhua; Li, Yanhua; Rowland, Bob; Renukaradhya, Gourapura J

2016-01-01

This review addresses important issues of porcine reproductive and respiratory syndrome virus (PRRSV) infection, immunity, pathogenesis, and control. Worldwide, PRRS is the most economically important infectious disease of pigs. We highlight the latest information on viral genome structure, pathogenic mechanisms, and host immunity, with a special focus on immune factors that modulate PRRSV infections during the acute and chronic/persistent disease phases. We address genetic control of host resistance and probe effects of PRRSV infection on reproductive traits. A major goal is to identify cellular/viral targets and pathways for designing more effective vaccines and therapeutics. Based on progress in viral reverse genetics, host transcriptomics and genomics, and vaccinology and adjuvant technologies, we have identified new areas for PRRS control and prevention. Finally, we highlight the gaps in our knowledge base and the need for advanced molecular and immune tools to stimulate PRRS research and field applications.

A structural equation modelling approach to explore the role of B vitamins and immune markers in lung cancer risk.

PubMed

Baltar, Valéria Troncoso; Xun, Wei W; Johansson, Mattias; Ferrari, Pietro; Chuang, Shu-Chun; Relton, Caroline; Ueland, Per Magne; Midttun, Øivind; Slimani, Nadia; Jenab, Mazda; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie-Christine; Fagherazzi, Guy; Kaaks, Rudolf; Rohrmann, Sabine; Boeing, Heiner; Weikert, Cornelia; Bueno-de-Mesquita, Bas; Boshuizen, Hendriek; van Gils, Carla H; Onland-Moret, N Charlotte; Agudo, Antonio; Barricarte, Aurelio; Navarro, Carmen; Rodríguez, Laudina; Castaño, José Maria Huerta; Larrañaga, Nerea; Khaw, Kay-Tee; Wareham, Nick; Allen, Naomi E; Crowe, Francesca; Gallo, Valentina; Norat, Teresa; Krogh, Vittorio; Masala, Giovanna; Panico, Salvatore; Sacerdote, Carlotta; Tumino, Rosario; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Rasmuson, Torgny; Hallmans, Göran; Roswall, Nina; Tjønneland, Anne; Riboli, Elio; Brennan, Paul; Vineis, Paolo

2013-08-01

The one-carbon metabolism (OCM) is considered key in maintaining DNA integrity and regulating gene expression, and may be involved in the process of carcinogenesis. Several B-vitamins and amino acids have been implicated in lung cancer risk, via the OCM directly as well as immune system activation. However it is unclear whether these factors act independently or through complex mechanisms. The current study applies structural equations modelling (SEM) to further disentangle the mechanisms involved in lung carcinogenesis. SEM allows simultaneous estimation of linear relations where a variable can be the outcome in one equation and the predictor in another, as well as allowing estimation using latent variables (factors estimated by correlation matrix). A large number of biomarkers have been analysed from 891 lung cancer cases and 1,747 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Four putative mechanisms in the OCM and immunity were investigated in relation to lung cancer risk: methionine-homocysteine metabolism, folate cycle, transsulfuration, and mechanisms involved in inflammation and immune activation, all adjusted for tobacco exposure. The hypothesized SEM model confirmed a direct and protective effect for factors representing methionine-homocysteine metabolism (p = 0.020) and immune activation (p = 0.021), and an indirect protective effect of folate cycle (p = 0.019), after adjustment for tobacco smoking. In conclusion, our results show that in the investigation of the involvement of the OCM, the folate cycle and immune system in lung carcinogenesis, it is important to consider complex pathways (by applying SEM) rather than the effects of single vitamins or nutrients (e.g. using traditional multiple regression). In our study SEM were able to suggest a greater role of the methionine-homocysteine metabolism and immune activation over other potential mechanisms.

Immune-modulatory effects of dietary Yeast Beta-1,3/1,6-D-glucan

PubMed Central

2014-01-01

Beta-glucans are a heterogeneous group of natural polysaccharides mostly investigated for their immunological effects. Due to the low systemic availability of oral preparations, it has been thought that only parenterally applied beta-glucans can modulate the immune system. However, several in vivo and in vitro investigations have revealed that orally applied beta-glucans also exert such effects. Various receptor interactions, explaining possible mode of actions, have been detected. The effects mainly depend on the source and structure of the beta-glucans. In the meantime, several human clinical trials with dietary insoluble yeast beta-glucans have been performed. The results confirm the previous findings of in vivo studies. The results of all studies taken together clearly indicate that oral intake of insoluble yeast beta-glucans is safe and has an immune strengthening effect. PMID:24774968

Abnormal Epigenetic Regulation of Immune System during Aging.

PubMed

Jasiulionis, Miriam G

2018-01-01

Epigenetics refers to the study of mechanisms controlling the chromatin structure, which has fundamental role in the regulation of gene expression and genome stability. Epigenetic marks, such as DNA methylation and histone modifications, are established during embryonic development and epigenetic profiles are stably inherited during mitosis, ensuring cell differentiation and fate. Under the effect of intrinsic and extrinsic factors, such as metabolic profile, hormones, nutrition, drugs, smoke, and stress, epigenetic marks are actively modulated. In this sense, the lifestyle may affect significantly the epigenome, and as a result, the gene expression profile and cell function. Epigenetic alterations are a hallmark of aging and diseases, such as cancer. Among biological systems compromised with aging is the decline of immune response. Different regulators of immune response have their promoters and enhancers susceptible to the modulation by epigenetic marks, which is fundamental to the differentiation and function of immune cells. Consistent evidence has showed the regulation of innate immune cells, and T and B lymphocytes by epigenetic mechanisms. Therefore, age-dependent alterations in epigenetic marks may result in the decline of immune function and this might contribute to the increased incidence of diseases in old people. In order to maintain health, we need to better understand how to avoid epigenetic alterations related to immune aging. In this review, the contribution of epigenetic mechanisms to the loss of immune function during aging will be discussed, and the promise of new means of disease prevention and management will be pointed.

Soy isoflavones and immunity.

PubMed

Sakai, Tohru; Kogiso, Mari

2008-08-01

The amount of soy products consumed in Japan is much greater than that in Western countries. Recent evidence indicates that soy isoflavones play a beneficial role in obesity, cancer, osteoporosis, and cardiovascular disease. The soybean isoflavone genistein is present at high levels in soy products. Genistein is structurally similar to 17beta-estradiol (E2), and genistein has been suggested to be act as E2 or an antagonist against E2. Genistein suppresses antigen-specific immune response in vivo and lymphocyte proliferation response in vitro. However, genistein enhances the cytotoxic response mediated by NK and cytotoxic T cells and the cytokine production from T cells. Thus, the effect of genistein on immunity is immune cell-dependent. Due to its unique effect on immune function, genistein has been used for the treatment of the diseases in animal models and it has been found that genistein inhibits allergic inflammatory responses. In this review, we summarize current studies related to the effect of isoflavone genistein on the immune system.

Enhancement of broodstock health and maternal immunity in gilthead seabream (Sparus aurata L.) using ExcelMOS®.

PubMed

AbouShabana, N M; AbdelKader, R; Abdel-Rahman, S; Abdel-Gawad, H S; Abdel-Galil, A M

2018-05-22

The current study was conducted to investigate the effect of ExcelMOS® in enhancing the immune system of Sparus aurata broodstock and their impact on offspring health through displaying the maternal transfer of immunity. Broodstock were divided into two groups: one was injected intraperitoneally with ExcelMOS® 1 month before spawning, while the other group was used as a control (without injection). Comprehensive increase in survival rate was observed for larvae hatched from ExcelMOS®-injected broodstock than those of the control (P ≤ 0.05). Hematological analysis showed increases in leukocyte count and hematocrit percentage (P ≤ 0.05) and significant enhancement in immune assays as phagocytic, respiratory burst, lysozyme activities in ExcelMOS®-injected broodstock (P ≤ 0.05). Additionally, total immunoglobulin levels in the serum, eggs, and larvae resulted from ExcelMOS®-injected broodstock were highly significant (P ≤ 0.05) than those in the control ones. Transmission electron microscopy and semi-thin sections in posterior intestine of ExcelMOS®-injected broodstock revealed reinforcement of the epithelial barrier structure, intestinal integrity, and functionality in combination with the stimulation of innate immune system. In conclusion, immunostimulation of Sparus aurata broodstock using ExcelMOS® has improved survival of larvae and enhanced both innate and adaptive immune defense mechanisms. Further investigations are required to show the effect of ExcelMOS® on fish cultured in intensive culture systems.

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

PubMed Central

Dinan, Timothy G; Cryan, John F

2017-01-01

There is now a large volume of evidence to support the view that the immune system is a key communication pathway between the gut and brain, which plays an important role in stress-related psychopathologies and thus provides a potentially fruitful target for psychotropic intervention. The gut microbiota is a complex ecosystem with a diverse range of organisms and a sophisticated genomic structure. Bacteria within the gut are estimated to weigh in excess of 1 kg in the adult human and the microbes within not only produce antimicrobial peptides, short chain fatty acids, and vitamins, but also most of the common neurotransmitters found in the human brain. That the microbial content of the gut plays a key role in immune development is now beyond doubt. Early disruption of the host-microbe interplay can have lifelong consequences, not just in terms of intestinal function but in distal organs including the brain. It is clear that the immune system and nervous system are in continuous communication in order to maintain a state of homeostasis. Significant gaps in knowledge remain about the effect of the gut microbiota in coordinating the immune-nervous systems dialogue. However, studies using germ-free animals, infective models, prebiotics, probiotics, and antibiotics have increased our understanding of the interplay. Early life stress can have a lifelong impact on the microbial content of the intestine and permanently alter immune functioning. That early life stress can also impact adult psychopathology has long been appreciated in psychiatry. The challenge now is to fully decipher the molecular mechanisms that link the gut microbiota, immune, and central nervous systems in a network of communication that impacts behavior patterns and psychopathology, to eventually translate these findings to the human situation both in health and disease. Even at this juncture, there is evidence to pinpoint key sites of communication where gut microbial interventions either with drugs or diet or perhaps fecal microbiota transplantation may positively impact mental health. PMID:27319972

Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach

PubMed Central

Sershen, Cheryl L.; Plimpton, Steven J.; May, Elebeoba E.

2016-01-01

Mycobacterium tuberculosis associated granuloma formation can be viewed as a structural immune response that can contain and halt the spread of the pathogen. In several mammalian hosts, including non-human primates, Mtb granulomas are often hypoxic, although this has not been observed in wild type murine infection models. While a presumed consequence, the structural contribution of the granuloma to oxygen limitation and the concomitant impact on Mtb metabolic viability and persistence remains to be fully explored. We develop a multiscale computational model to test to what extent in vivo Mtb granulomas become hypoxic, and investigate the effects of hypoxia on host immune response efficacy and mycobacterial persistence. Our study integrates a physiological model of oxygen dynamics in the extracellular space of alveolar tissue, an agent-based model of cellular immune response, and a systems biology-based model of Mtb metabolic dynamics. Our theoretical studies suggest that the dynamics of granuloma organization mediates oxygen availability and illustrates the immunological contribution of this structural host response to infection outcome. Furthermore, our integrated model demonstrates the link between structural immune response and mechanistic drivers influencing Mtbs adaptation to its changing microenvironment and the qualitative infection outcome scenarios of clearance, containment, dissemination, and a newly observed theoretical outcome of transient containment. We observed hypoxic regions in the containment granuloma similar in size to granulomas found in mammalian in vivo models of Mtb infection. In the case of the containment outcome, our model uniquely demonstrates that immune response mediated hypoxic conditions help foster the shift down of bacteria through two stages of adaptation similar to thein vitro non-replicating persistence (NRP) observed in the Wayne model of Mtb dormancy. The adaptation in part contributes to the ability of Mtb to remain dormant for years after initial infection. PMID:26913242

Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach.

PubMed

Sershen, Cheryl L; Plimpton, Steven J; May, Elebeoba E

2016-01-01

Mycobacterium tuberculosis associated granuloma formation can be viewed as a structural immune response that can contain and halt the spread of the pathogen. In several mammalian hosts, including non-human primates, Mtb granulomas are often hypoxic, although this has not been observed in wild type murine infection models. While a presumed consequence, the structural contribution of the granuloma to oxygen limitation and the concomitant impact on Mtb metabolic viability and persistence remains to be fully explored. We develop a multiscale computational model to test to what extent in vivo Mtb granulomas become hypoxic, and investigate the effects of hypoxia on host immune response efficacy and mycobacterial persistence. Our study integrates a physiological model of oxygen dynamics in the extracellular space of alveolar tissue, an agent-based model of cellular immune response, and a systems biology-based model of Mtb metabolic dynamics. Our theoretical studies suggest that the dynamics of granuloma organization mediates oxygen availability and illustrates the immunological contribution of this structural host response to infection outcome. Furthermore, our integrated model demonstrates the link between structural immune response and mechanistic drivers influencing Mtbs adaptation to its changing microenvironment and the qualitative infection outcome scenarios of clearance, containment, dissemination, and a newly observed theoretical outcome of transient containment. We observed hypoxic regions in the containment granuloma similar in size to granulomas found in mammalian in vivo models of Mtb infection. In the case of the containment outcome, our model uniquely demonstrates that immune response mediated hypoxic conditions help foster the shift down of bacteria through two stages of adaptation similar to the in vitro non-replicating persistence (NRP) observed in the Wayne model of Mtb dormancy. The adaptation in part contributes to the ability of Mtb to remain dormant for years after initial infection.

Biological response modifiers: their possibilities for cancer treatment.

PubMed

Franz, G

1989-01-01

Immunotherapy with the so-called 'Biological Response Modifiers' is based on the concept that the immune system can be activated to control neoplastic growth. Immunotherapy gained popularity as a treatment in the 1960's because of data from experimental tumor models. This indicated that mainly nonspecific stimulation with products of bacterial or fungal origine could prevent recurrence of, or delay growth of experimentally transplanted tumors. Since immunotherapy was most effective against relatively small tumors, clinical investigators began to view it mainly as a post-surgical treatment for a inhibition of micrometastasis. Mainly the activation of the non specific killer cells, macrophages and lymphocytes seems very promising to target an immune stimulant in the tumor site with a relatively high specificity. In the present study a whole series of biological polymers were tested in view of their capacity to enhance the immune system. However, the relatively small number of such compounds which can be applied therapeutically demonstrates that the ability of a compound to stimulate the immune systems is dependent on several conditions, such as the molecular dimension, the structure type and the solubility criteria. It will be shown that specific fungal glucans are very promising candidates for a successful cancer treatment.

Structural and functional annotation of the porcine immunome

PubMed Central

2013-01-01

Background The domestic pig is known as an excellent model for human immunology and the two species share many pathogens. Susceptibility to infectious disease is one of the major constraints on swine performance, yet the structure and function of genes comprising the pig immunome are not well-characterized. The completion of the pig genome provides the opportunity to annotate the pig immunome, and compare and contrast pig and human immune systems. Results The Immune Response Annotation Group (IRAG) used computational curation and manual annotation of the swine genome assembly 10.2 (Sscrofa10.2) to refine the currently available automated annotation of 1,369 immunity-related genes through sequence-based comparison to genes in other species. Within these genes, we annotated 3,472 transcripts. Annotation provided evidence for gene expansions in several immune response families, and identified artiodactyl-specific expansions in the cathelicidin and type 1 Interferon families. We found gene duplications for 18 genes, including 13 immune response genes and five non-immune response genes discovered in the annotation process. Manual annotation provided evidence for many new alternative splice variants and 8 gene duplications. Over 1,100 transcripts without porcine sequence evidence were detected using cross-species annotation. We used a functional approach to discover and accurately annotate porcine immune response genes. A co-expression clustering analysis of transcriptomic data from selected experimental infections or immune stimulations of blood, macrophages or lymph nodes identified a large cluster of genes that exhibited a correlated positive response upon infection across multiple pathogens or immune stimuli. Interestingly, this gene cluster (cluster 4) is enriched for known general human immune response genes, yet contains many un-annotated porcine genes. A phylogenetic analysis of the encoded proteins of cluster 4 genes showed that 15% exhibited an accelerated evolution as compared to 4.1% across the entire genome. Conclusions This extensive annotation dramatically extends the genome-based knowledge of the molecular genetics and structure of a major portion of the porcine immunome. Our complementary functional approach using co-expression during immune response has provided new putative immune response annotation for over 500 porcine genes. Our phylogenetic analysis of this core immunome cluster confirms rapid evolutionary change in this set of genes, and that, as in other species, such genes are important components of the pig’s adaptation to pathogen challenge over evolutionary time. These comprehensive and integrated analyses increase the value of the porcine genome sequence and provide important tools for global analyses and data-mining of the porcine immune response. PMID:23676093

The influence of intrauterine exposure to immunosuppressive treatment on changes in the immune system in juvenile Wistar rats.

PubMed

Kabat-Koperska, Joanna; Kolasa-Wołosiuk, Agnieszka; Wojciuk, Bartosz; Wojciechowska-Koszko, Iwona; Roszkowska, Paulina; Krasnodębska-Szponder, Barbara; Paczkowska, Edyta; Safranow, Krzysztof; Gołembiewska, Edyta; Machaliński, Bogusław; Ciechanowski, Kazimierz

2016-01-01

In our study, we assessed the impact of immunosuppressive drug combinations on changes in the immune system of juvenile Wistar rats exposed to these drugs during pregnancy. We primarily concentrated on changes in two organs of the immune system - the thymus and the spleen. The study was conducted on 40 (32+8) female Wistar rats administered full and half dose of drugs, respectively, subjected to regimens commonly used in therapy of human kidney transplant recipients ([1] cyclosporine A, mycophenolate mofetil, and prednisone; [2] tacrolimus, mycophenolate mofetil, and prednisone; [3] cyclosporine A, everolimus, and prednisone). The animals received drugs by oral gavage 2 weeks before pregnancy and during 3 weeks of pregnancy. There were no statistically significant differences in the weight of the thymus and spleen, but changes were found in the results of blood hematology, cytometry from the spleen, and a histologic examination of the examined immune organs of juvenile Wistar rats. In the cytokine assay, changes in the level of interleukine 17 (IL-17) after increasing amounts of concanavaline A were dose-dependent; the increase of IL-17 was blocked after administration of higher doses of immunosuppressive drugs. However, after a reduction of doses, its increase resumed. Qualitative, quantitative, and morphological changes in the immune system of infant rats born to pharmacologically immunosuppressed females were observed. Thymus structure, spleen composition, and splenocyte IL-17 production were mostly affected in a drug regimen-dependent manner.

Toxoplasmosis presenting as panhypopituitarism in a patient with the acquired immune deficiency syndrome.

PubMed

Milligan, S A; Katz, M S; Craven, P C; Strandberg, D A; Russell, I J; Becker, R A

1984-10-01

A 57-year-old man with a prior episode of lymphatic toxoplasmosis presented with signs of anterior panhypopituitarism, which was confirmed by standard endocrinologic evaluation. The diagnosis of central nervous system toxoplasmosis was established by brain biopsy after nondiagnostic serologic and radiographic studies. At autopsy, the anterior pituitary was necrotic, with Toxoplasma abscesses in neighboring brain structures. Clinical and laboratory data met the criteria for the acquired immune deficiency syndrome. Although this is the first reported case of toxoplasmosis presenting as panhypopituitarism, future cases may be identified since central nervous system toxoplasmosis is being recognized more frequently in patients with immunodeficiency.

Cutaneous immunology: basics and new concepts.

PubMed

Yazdi, Amir S; Röcken, Martin; Ghoreschi, Kamran

2016-01-01

As one of the largest organs, the skin forms a mechanical and immunological barrier to the environment. The skin immune system harbors cells of the innate immune system and cells of the adaptive immune system. Signals of the innate immune system typically initiate skin immune responses, while cells and cytokines of the adaptive immune system perpetuate the inflammation. Skin immune responses ensure effective host defense against pathogens but can also cause inflammatory skin diseases. An extensive crosstalk between the different cell types of the immune system, tissue cells, and pathogens is responsible for the complexity of skin immune reactions. Here we summarize the major cellular and molecular components of the innate and adaptive skin immune system.

Mechanisms of lung aging.

PubMed

Brandenberger, Christina; Mühlfeld, Christian

2017-03-01

Lung aging is associated with structural remodeling, a decline of respiratory function and a higher susceptibility to acute and chronic lung diseases. Individual factors that modulate pulmonary aging include basic genetic configuration, environmental exposure, life-style and biography of systemic diseases. However, the actual aging of the lung takes place in pulmonary resident cells and is closely linked to aging of the immune system (immunosenescence). Therefore, this article reviews the current knowledge about the impact of aging on pulmonary cells and the immune system, without analyzing those factors that may accelerate the aging process in depth. Hallmarks of aging include alterations at molecular, cellular and cell-cell interaction levels. Because of the great variety of cell types in the lung, the consequences of aging display a broad spectrum of phenotypes. For example, aging is associated with more collagen and less elastin production by fibroblasts, thus increasing pulmonary stiffness and lowering compliance. Decreased sympathetic airway innervation may increase the constriction status of airway smooth muscle cells. Aging of resident and systemic immune cells leads to a pro-inflammatory milieu and reduced capacity of fighting infectious diseases. The current review provides an overview of cellular changes occurring with advancing age in general and in several cell types of the lung as well as of the immune system. Thereby, this survey not only aims at providing a better understanding of the mechanisms of pulmonary aging but also to identify gaps in knowledge that warrant further investigations.

[The extraneuronal cholinergic system of the skin. Basic facts and clinical relevance].

PubMed

Kurzen, H

2004-05-01

Acetylcholine (ACh) is a prototypical neurotransmitter that has recently been recognized to occur extraneuronally in a large variety of cells. ACh and its nicotinic and muscarinic receptors are produced in the epidermis and in the adnexal structures of the skin in a highly complicated pattern. They are also produced in melanocytes, fibroblasts, endothelial cells and immune cells. Through autocrine, paracrine and endocrine mechanisms, the cholinergic system is involved in the basic functions of the skin, such as keratinocyte differentiation, epidermal barrier formation, sweating, sebum production, blood circulation, angiogenesis and a variety of immune reactions. Hence diseases like acne vulgaris, vitiligo, psoriasis, pemphigus vulgaris and atopic dermatitis may be influenced. The exploration of the extraneuronal cholinergic system of the skin has only just begun.

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

The development of pathogen resistance in Daphnia magna: implications for disease spread in age-structured populations.

PubMed

Garbutt, Jennie S; O'Donoghue, Anna J P; McTaggart, Seanna J; Wilson, Philip J; Little, Tom J

2014-11-01

Immunity in vertebrates is well established to develop with time, but the ontogeny of defence in invertebrates is markedly less studied. Yet, age-specific capacity for defence against pathogens, coupled with age structure in populations, has widespread implications for disease spread. Thus, we sought to determine the susceptibility of hosts of different ages in an experimental invertebrate host-pathogen system. In a series of experiments, we show that the ability of Daphnia magna to resist its natural bacterial pathogen Pasteuria ramosa changes with host age. Clonal differences make it difficult to draw general conclusions, but the majority of observations indicate that resistance increases early in the life of D. magna, consistent with the idea that the defence system develops with time. Immediately following this, at about the time when a daphnid would be most heavily investing in reproduction, resistance tends to decline. Because many ecological factors influence the age structure of Daphnia populations, our results highlight a broad mechanism by which ecological context can affect disease epidemiology. We also show that a previously observed protective effect of restricted maternal food persists throughout the entire juvenile period, and that the protective effect of prior treatment with a small dose of the pathogen ('priming') persists for 7 days, observations that reinforce the idea that immunity in D. magna can change over time. Together, our experiments lead us to conclude that invertebrate defence capabilities have an ontogeny that merits consideration with respect to both their immune systems and the epidemic spread of infection. © 2014. Published by The Company of Biologists Ltd.

The development of pathogen resistance in Daphnia magna: implications for disease spread in age-structured populations

PubMed Central

Garbutt, Jennie S.; O'Donoghue, Anna J. P.; McTaggart, Seanna J.; Wilson, Philip J.; Little, Tom J.

2014-01-01

Immunity in vertebrates is well established to develop with time, but the ontogeny of defence in invertebrates is markedly less studied. Yet, age-specific capacity for defence against pathogens, coupled with age structure in populations, has widespread implications for disease spread. Thus, we sought to determine the susceptibility of hosts of different ages in an experimental invertebrate host–pathogen system. In a series of experiments, we show that the ability of Daphnia magna to resist its natural bacterial pathogen Pasteuria ramosa changes with host age. Clonal differences make it difficult to draw general conclusions, but the majority of observations indicate that resistance increases early in the life of D. magna, consistent with the idea that the defence system develops with time. Immediately following this, at about the time when a daphnid would be most heavily investing in reproduction, resistance tends to decline. Because many ecological factors influence the age structure of Daphnia populations, our results highlight a broad mechanism by which ecological context can affect disease epidemiology. We also show that a previously observed protective effect of restricted maternal food persists throughout the entire juvenile period, and that the protective effect of prior treatment with a small dose of the pathogen (‘priming’) persists for 7 days, observations that reinforce the idea that immunity in D. magna can change over time. Together, our experiments lead us to conclude that invertebrate defence capabilities have an ontogeny that merits consideration with respect to both their immune systems and the epidemic spread of infection. PMID:25214486

Introduction of Inactivated Polio Vaccine, Withdrawal of Type 2 Oral Polio Vaccine, and Routine Immunization Strengthening in the Eastern Mediterranean Region.

PubMed

Fahmy, Kamal; Hampton, Lee M; Langar, Houda; Patel, Manish; Mir, Tahir; Soloman, Chandrasegarar; Hasman, Andreas; Yusuf, Nasir; Teleb, Nadia

2017-07-01

The Global Polio Eradication Initiative has reduced the global incidence of polio by 99% and the number of countries with endemic polio from 125 to 3 countries. The Polio Eradication and Endgame Strategic Plan 2013-2018 (Endgame Plan) was developed to end polio disease. Key elements of the endgame plan include strengthening immunization systems using polio assets, introducing inactivated polio vaccine (IPV), and replacing trivalent oral polio vaccine with bivalent oral polio vaccine ("the switch"). Although coverage in the Eastern Mediterranean Region (EMR) with the third dose of a vaccine containing diphtheria, tetanus, and pertussis antigens (DTP3) was ≥90% in 14 countries in 2015, DTP3 coverage in EMR dropped from 86% in 2010 to 80% in 2015 due to civil disorder in multiple countries. To strengthen their immunization systems, Pakistan, Afghanistan, and Somalia developed draft plans to integrate Polio Eradication Initiative assets, staff, structure, and activities with their Expanded Programmes on Immunization, particularly in high-risk districts and regions. Between 2014 and 2016, 11 EMR countries introduced IPV in their routine immunization program, including all of the countries at highest risk for polio transmission (Afghanistan, Pakistan, Somalia, and Yemen). As a result, by the end of 2016 all EMR countries were using IPV except Egypt, where introduction of IPV was delayed by a global shortage. The switch was successfully implemented in EMR due to the motivation, engagement, and cooperation of immunization staff and decision makers across all national levels. Moreover, the switch succeeded because of the ability of even the immunization systems operating under hardship conditions of conflict to absorb the switch activities. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

An XA21-Associated Kinase (OsSERK2) Regulates Immunity Mediated by the XA21 and XA3 Immune Receptors

PubMed Central

Chen, Xuewei; Zuo, Shimin; Schwessinger, Benjamin; Chern, Mawsheng; Canlas, Patrick E.; Ruan, Deling; Zhou, Xiaogang; Wang, Jing; Daudi, Arsalan; Petzold, Christopher J.; Heazlewood, Joshua L.; Ronald, Pamela C.

2014-01-01

The rice XA21 immune receptor kinase and the structurally related XA3 receptor confer immunity to Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial leaf blight. Here we report the isolation of OsSERK2 (rice somatic embryogenesis receptor kinase 2) and demonstrate that OsSERK2 positively regulates immunity mediated by XA21 and XA3 as well as the rice immune receptor FLS2 (OsFLS2). Rice plants silenced for OsSerk2 display altered morphology and reduced sensitivity to the hormone brassinolide. OsSERK2 interacts with the intracellular domains of each immune receptor in the yeast two-hybrid system in a kinase activity-dependent manner. OsSERK2 undergoes bidirectional transphosphorylation with XA21 in vitro and forms a constitutive complex with XA21 in vivo. These results demonstrate an essential role for OsSERK2 in the function of three rice immune receptors and suggest that direct interaction with the rice immune receptors is critical for their function. Taken together, our findings suggest that the mechanism of OsSERK2-meditated regulation of rice XA21, XA3, and FLS2 differs from that of AtSERK3/BAK1-mediated regulation of Arabidopsis FLS2 and EFR. PMID:24482436

[Eye-associated lymphoid tissue (EALT) is continuously spread throughout the ocular surface from the lacrimal gland to the lacrimal drainage system].

PubMed

Knop, E; Knop, N

2003-11-01

Components of the mucosal immune system (MALT) have been identified in the conjunctiva (as CALT) and the lacrimal drainage system (as LDALT). Their structural and functional relation with the established immune protection by the lacrimal gland is unclear. Macroscopically normal and complete tissues of the conjunctiva, lacrimal drainage system and lacrimal gland from human body donors were investigated by analysis of translucent whole mounts, and using histology, immunohistology as well as scanning and transmission electron microscopy. A typical diffuse lymphoid tissue, composed of effector cells of the immune system (T-lymphocytes and IgA producing plasma cells) under an epithelium that contains the IgA transporter SC, is not isolated in the conjunctiva and lacrimal drainage system. It is anatomically continuous from the lacrimal gland along its excretory ducts into the conjunctiva and from there via the lacrimal canaliculi into the lacrimal drainage system. Lymphoid follicles occur in a majority (about 60%) and with bilateral symmetry. The topography of CALT corresponds to the position of the cornea in the closed eye. These results show that the MALT of the lacrimal gland, conjunctiva and lacrimal drainage system constitute an anatomical and functional unit for immune protection of the ocular surface. Therefore it should be integrated as an "eye-associated lymphoid tissue" (EALT) into the MALT system of the body. EALT can detect ocular surface antigens by the lymphoid follicles and can supply other organs and the ocular surface including the lacrimal gland with specific effector cells via the regulated recirculation of lymphoid cells.

(Neuro)transmitter systems in circulating immune cells: a target of immunopharmacological interventions?

PubMed

Tayebati, Seyed Khosrow; Amenta, Francesco

2008-01-01

Increasing evidence indicates the existence of an association between nervous and immune systems. The two systems communicate with each-other to maintain immune homeostasis. Activated immune cells secrete cytokines that influence central nervous system activity. Nervous system, through its peripheral and/or autonomic divisions activates output regulating levels of immune cell activity and the subsequent magnitude of an immune response. On the other hand, neurotransmitters, which represent the main substances involved in nerve cell communications, can influence immune function. Immune organs and circulating immune cells express several (neuro)transmitter systems that can be involved in regulating their activity. The expression of neurotransmitter systems by different subsets of circulating immune cells was reviewed. The regulatory role of different families of (neuro)transmitters (catecholamines, 5-hydroxytryptamine, acetylcholine, histamine and neuropeptides) in modulating levels of immune mediators or specific immune responses is discussed.

Canine Parvovirus VP2 Protein Expressed in Silkworm Pupae Self-Assembles into Virus-Like Particles with High Immunogenicity

PubMed Central

Wang, Hua-lei; Liang, Meng; Liang, Hongru; Guo, He; Zhao, Pingsen; Yang, Yu-jiao; Zheng, Xue-xing; Zhang, Zhi-fang; Zhao, Yong-kun; Gao, Yu-wei; Yang, Song-tao; Xia, Xian-zhu

2014-01-01

The VP2 structural protein of parvovirus can produce virus-like particles (VLPs) by a self-assembly process in vitro, making VLPs attractive vaccine candidates. In this study, the VP2 protein of canine parvovirus (CPV) was expressed using a baculovirus expression system and assembled into parvovirus-like particles in insect cells and pupae. Electron micrographs of VLPs showed that they were very similar in size and morphology when compared to the wild-type parvovirus. The immunogenicity of the VLPs was investigated in mice and dogs. Mice immunized intramuscularly with purified VLPs, in the absence of an adjuvant, elicited CD4+ and CD8+ T cell responses and were able to elicit a neutralizing antibody response against CPV, while the oral administration of raw homogenates containing VLPs to the dogs resulted in a systemic immune response and long-lasting immunity. These results demonstrate that the CPV-VLPs stimulate both cellular and humoral immune responses, and so CPV-VLPs may be a promising candidate vaccine for the prevention of CPV-associated disease. PMID:24465364

Canine parvovirus VP2 protein expressed in silkworm pupae self-assembles into virus-like particles with high immunogenicity.

PubMed

Feng, Hao; Hu, Gui-qiu; Wang, Hua-lei; Liang, Meng; Liang, Hongru; Guo, He; Zhao, Pingsen; Yang, Yu-jiao; Zheng, Xue-xing; Zhang, Zhi-fang; Zhao, Yong-kun; Gao, Yu-wei; Yang, Song-tao; Xia, Xian-zhu

2014-01-01

The VP2 structural protein of parvovirus can produce virus-like particles (VLPs) by a self-assembly process in vitro, making VLPs attractive vaccine candidates. In this study, the VP2 protein of canine parvovirus (CPV) was expressed using a baculovirus expression system and assembled into parvovirus-like particles in insect cells and pupae. Electron micrographs of VLPs showed that they were very similar in size and morphology when compared to the wild-type parvovirus. The immunogenicity of the VLPs was investigated in mice and dogs. Mice immunized intramuscularly with purified VLPs, in the absence of an adjuvant, elicited CD4(+) and CD8(+) T cell responses and were able to elicit a neutralizing antibody response against CPV, while the oral administration of raw homogenates containing VLPs to the dogs resulted in a systemic immune response and long-lasting immunity. These results demonstrate that the CPV-VLPs stimulate both cellular and humoral immune responses, and so CPV-VLPs may be a promising candidate vaccine for the prevention of CPV-associated disease.

Human neutrophils in auto-immunity.

PubMed

Thieblemont, Nathalie; Wright, Helen L; Edwards, Steven W; Witko-Sarsat, Véronique

2016-04-01

Human neutrophils have great capacity to cause tissue damage in inflammatory diseases via their inappropriate activation to release reactive oxygen species (ROS), proteases and other tissue-damaging molecules. Furthermore, activated neutrophils can release a wide variety of cytokines and chemokines that can regulate almost every element of the immune system. In addition to these important immuno-regulatory processes, activated neutrophils can also release, expose or generate neoepitopes that have the potential to break immune tolerance and result in the generation of autoantibodies, that characterise a number of human auto-immune diseases. For example, in vasculitis, anti-neutrophil cytoplasmic antibodies (ANCA) that are directed against proteinase 3 or myeloperoxidase are neutrophil-derived autoantigens and activated neutrophils are the main effector cells of vascular damage. In other auto-immune diseases, these neutrophil-derived neoepitopes may arise from a number of processes that include release of granule enzymes and ROS, changes in the properties of components of their plasma membrane as a result of activation or apoptosis, and via the release of Neutrophil Extracellular Traps (NETs). NETs are extracellular structures that contain chromatin that is decorated with granule enzymes (including citrullinated proteins) that can act as neo-epitopes to generate auto-immunity. This review therefore describes the processes that can result in neutrophil-mediated auto-immunity, and the role of neutrophils in the molecular pathologies of auto-immune diseases such as vasculitis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We discuss the potential role of NETs in these processes and some of the debate in the literature regarding the role of this phenomenon in microbial killing, cell death and auto-immunity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Kdo2-lipid A: structural diversity and impact on immunopharmacology

PubMed Central

Wang, Xiaoyuan; Quinn, Peter J; Yan, Aixin

2015-01-01

3-deoxy-d-manno-octulosonic acid-lipid A (Kdo2-lipid A) is the essential component of lipopolysaccharide in most Gram-negative bacteria and the minimal structural component to sustain bacterial viability. It serves as the active component of lipopolysaccharide to stimulate potent host immune responses through the complex of Toll-like-receptor 4 (TLR4) and myeloid differentiation protein 2. The entire biosynthetic pathway of Escherichia coli Kdo2-lipid A has been elucidated and the nine enzymes of the pathway are shared by most Gram-negative bacteria, indicating conserved Kdo2-lipid A structure across different species. Yet many bacteria can modify the structure of their Kdo2-lipid A which serves as a strategy to modulate bacterial virulence and adapt to different growth environments as well as to avoid recognition by the mammalian innate immune systems. Key enzymes and receptors involved in Kdo2-lipid A biosynthesis, structural modification and its interaction with the TLR4 pathway represent a clear opportunity for immunopharmacological exploitation. These include the development of novel antibiotics targeting key biosynthetic enzymes and utilization of structurally modified Kdo2-lipid A or correspondingly engineered live bacteria as vaccines and adjuvants. Kdo2-lipid A/TLR4 antagonists can also be applied in anti-inflammatory interventions. This review summarizes recent knowledge on both the fundamental processes of Kdo2-lipid A biosynthesis, structural modification and immune stimulation, and applied research on pharmacological exploitations of these processes for therapeutic development. PMID:24838025

The Immune System: Basis of so much Health and Disease: 2. Innate Immunity.

PubMed

Scully, Crispian; Georgakopoulou, Eleni A; Hassona, Yazan

2017-03-01

The immune system is the body’s primary defence mechanism against infections, and disturbances in the system can cause disease if the system fails in defence functions (in immunocompromised people), or if the activity is detrimental to the host (as in auto-immune and auto-inflammatory states). A healthy immune system is also essential to normal health of dental and oral tissues. This series presents the basics for the understanding of the immune system, this article covering innate immunity. Clinical relevance: Modern dental clinicians need a basic understanding of the immune system as it underlies health and disease.

The Immune System: Basis of so much Health and Disease: 3. Adaptive Immunity.

PubMed

Scully, Crispian; Georgakopoulou, Eleni A; Hassona, Yazan

2017-04-01

The immune system is the body’s primary defence mechanism against infections, and disturbances in the system can cause disease if the system fails in defence functions (in immunocompromised people), or if the activity is detrimental to the host (as in auto-immune and auto-inflammatory states). A healthy immune system is also essential to normal health of dental and oral tissues. This series presents the basics for the understanding of the immune system; this article covers adaptive immunity. Clinical relevance: Dental clinicians need a basic understanding of the immune system as it underlies health and disease.

Hiding in plain sight: immune evasion by the staphylococcal protein SdrE.

PubMed

Herr, Andrew B; Thorman, Alexander W

2017-05-10

The human immune system is responsible for identification and destruction of invader cells, such as the bacterial pathogen Staphylococcus aureus In response, S. aureus brings to the fight a large number of virulence factors, including several that allow it to evade the host immune response. The staphylococcal surface protein SdrE was recently reported to bind to complement Factor H, an important regulator of complement activation. Factor H attaches to the surface of host cells to inhibit complement activation and amplification, preventing the destruction of the host cell. SdrE binding to Factor H allows S. aureus to mimic a host cell and reduces bacterial killing by granulocytes. In a new study published in Biochemical Journal , Zhang et al. describe crystal structures of SdrE and its complex with the C-terminal portion of Factor H. The structure of SdrE and its interaction with the Factor H peptide closely resemble a family of surface proteins that recognize extracellular matrix components such as fibrinogen. However, unbound SdrE forms a novel 'Closed' conformation with an occluded peptide-binding groove. These structures reveal a fascinating mechanism for immune evasion and provide a potential avenue for the development of novel antimicrobial agents to target SdrE. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Structural insights into the inactivation of CRISPR-Cas systems by diverse anti-CRISPR proteins.

PubMed

Zhu, Yuwei; Zhang, Fan; Huang, Zhiwei

2018-03-19

A molecular arms race is progressively being unveiled between prokaryotes and viruses. Prokaryotes utilize CRISPR-mediated adaptive immune systems to kill the invading phages and mobile genetic elements, and in turn, the viruses evolve diverse anti-CRISPR proteins to fight back. The structures of several anti-CRISPR proteins have now been reported, and here we discuss their structural features, with a particular emphasis on topology, to discover their similarities and differences. We summarize the CRISPR-Cas inhibition mechanisms of these anti-CRISPR proteins in their structural context. Considering anti-CRISPRs in this way will provide important clues for studying their origin and evolution.

Systemic Inflammatory and Th17 Immune Activation among Patients Treated for Lumbar Radiculopathy Exceeds that of Patients Treated for Persistent Postoperative Neuropathic Pain.

PubMed

Shamji, Mohammed F; Guha, Daipayan; Paul, Darcia; Shcharinsky, Alina

2017-09-01

The pathophysiology of lumbar radiculopathy includes both mechanical compression and biochemical irritation of apposed neural elements. Inflammatory and immune cytokines have been implicated, induced by systemic exposure of immune-privileged intervertebral disc tissue. Surgical intervention provides improved symptoms and quality of life, but persistent postoperative neuropathic pain (PPNP) afflicts a significant fraction of patients. To compare the inflammatory and immune phenotypes among patients undergoing structural surgery for lumbar radiculopathy and spinal cord stimulation for neuropathic pain. Consecutive patients undergoing surgical intervention for lumbar radiculopathy or neuropathic pain were studied. Demographic data included age, gender, and VAS and neuropathic pain scores. Serum was evaluated for cytokine levels (IL-6, Il-17, TNF-α) and cellular content [white blood cell (WBC)/differential, lymphocyte subtypes]. The primary analysis differentiated molecular and cellular profiles between radiculopathy and neuropathic pain patients. Subgroup analysis within the surgical radiculopathy population compared those patients achieving relief of symptoms and those with PPNP. Heightened IL-6, Il-17, and TNF-α levels were observed for the lumbar radiculopathy group compared with the neuropathic pain group. This was complemented by higher WBC count and a greater fraction of Th17 lymphocytes among radiculopathy patients. In the lumbar discectomy subgroup, pain relief was seen among patients with preoperatively elevated IL-17 levels. Those patients with PPNP refractory to surgical discectomy exhibited normal cytokine levels. Differences in Th17 immune activation are seen among radiculopathy and neuropathic pain patients. These cellular and molecular profiles may be translated into biomarkers to improve patient selection for structural spine surgery. Copyright © 2017 by the Congress of Neurological Surgeons

[The liver and the immune system].

PubMed

Jakab, Lajos

2015-07-26

The liver is known to be the metabolic centre of the organism and is under the control of the central nervous system. It has a peculiar tissue structure and its anatomic localisation defines it as part of the immune system having an individual role in the defence of the organism. The determinant of its particular tissue build-up is the sinusoid system. In addition to hepatocytes, one cell row "endothelium", stellate cells close to the external surface, Kupffer cells tightly to its inner surface, as well as dendritic cells and other cell types (T and B lymphocytes, natural killer and natural killer T-cells, mast cells, granulocytes) are present. The multitudes and variety of cells make it possible to carry out the tasks according to the assignment of the organism. The liver is a member of the immune system having immune cells largely in an activated state. Its principal tasks are the assurance of the peripheral immune tolerance of the organism with the help of the haemopoetic cells and transforming growth factor-β. The liver takes part in the determination of the manner of the non-specific immune response of the organism. In addition to acute phase reaction of the organism, the liver has a role in the adaptive/specific immune response. These functions include retardation of the T and B lymphocytes and the defence against harmful pathogens. With the collaboration of transforming growth factor-β, immunoglobulins and their subclasses are inhibited just as the response of the T lymphocytes. The only exception is the undisturbed immunoglobulin A production. Particularly important is the intensive participation of the liver in the acute phase reaction of the organism, which is organised and guided by the coordinated functions of the cortico-hypothalamo-hypophysis-adrenal axis. Beside cellular elements, hormones, adhesion molecules, chemokines and cytokines are also involved in the cooperation with the organs. Acute phase reactants play a central role in these processes. Until recently the α2-macroglobulin was not considered as an acute reactant of the organism, but it is now functionally included in the acute phase reaction presumably due to its close connection with the transforming growth factor-β. Transforming growth factor-β has extraordinarily important roles in all phases of inflammation and in the specific immune response. The peripheral immune tolerance of the organism involves tightly coupled regulation of proliferation, differentiation and survival of lymphocytes.

Structural map of Kaposi sarcoma-associated herpesvirus RNA provides clues to molecular interactions | Center for Cancer Research

Cancer.gov

Scientists from CCR have generated a comprehensive structural map of Kaposi sarcoma-associated herpesvirus polyadenylated nuclear (PAN) RNA, a long non-coding RNA that helps the virus evade detection by its host’s immune system. The findings open new oppportunites to study the life cycle of this cancer-causing virus.  Learn more...

Chemometric Analysis of Bacterial Peptidoglycan Reveals Atypical Modifications That Empower the Cell Wall against Predatory Enzymes and Fly Innate Immunity.

PubMed

Espaillat, Akbar; Forsmo, Oskar; El Biari, Khouzaima; Björk, Rafael; Lemaitre, Bruno; Trygg, Johan; Cañada, Francisco Javier; de Pedro, Miguel A; Cava, Felipe

2016-07-27

Peptidoglycan is a fundamental structure for most bacteria. It contributes to the cell morphology and provides cell wall integrity against environmental insults. While several studies have reported a significant degree of variability in the chemical composition and organization of peptidoglycan in the domain Bacteria, the real diversity of this polymer is far from fully explored. This work exploits rapid ultraperformance liquid chromatography and multivariate data analysis to uncover peptidoglycan chemical diversity in the Class Alphaproteobacteria, a group of Gram negative bacteria that are highly heterogeneous in terms of metabolism, morphology and life-styles. Indeed, chemometric analyses revealed novel peptidoglycan structures conserved in Acetobacteria: amidation at the α-(l)-carboxyl of meso-diaminopimelic acid and the presence of muropeptides cross-linked by (1-3) l-Ala-d-(meso)-diaminopimelate cross-links. Both structures are growth-controlled modifications that influence sensitivity to Type VI secretion system peptidoglycan endopeptidases and recognition by the Drosophila innate immune system, suggesting relevant roles in the environmental adaptability of these bacteria. Collectively our findings demonstrate the discriminative power of chemometric tools on large cell wall-chromatographic data sets to discover novel peptidoglycan structural properties in bacteria.

Immunostimulant effects and potential application of β-glucans derived from marine yeast Debaryomyces hansenii in goat peripheral blood leucocytes.

PubMed

Medina-Córdova, Noé; Reyes-Becerril, Martha; Ascencio, Felipe; Castellanos, Thelma; Campa-Córdova, Angel I; Angulo, Carlos

2018-05-12

Debaryomyces hansenii has been described to be effective probiotic and immunostimulatory marine yeast in fish. Nonetheless, to the best of our knowledge, it has been not assayed in ruminants. This study attempts to describe the immunostimulatory effects of its β-glucan content through in vitro assays using goat peripheral blood leukocytes at 24 h of stimulation. The structural characterization of yeast glucans by proton nuclear magnetic resonance indicated structures containing (1-6)-branched (1-3)-β-D-glucan. In vitro assays using peripheral blood leukocytes stimulated with β-glucans derived from three D. hansenii strains and zymosan revealed that β-glucans significantly increased cell immune parameters, such as phagocytic ability, reactive oxygen species production (respiratory burst), peroxidase activity and nitric oxide production. Antioxidant enzymes revealed an increase in superoxide dismutase and catalase activities in leukocytes stimulated with yeast β-glucans. This study revealed that yeast β-glucans were able to activate dectin-1 mRNA gene expression in leukocytes. The TLR4 gene expression was up-regulated in leukocytes after stimulation with yeast β-glucans. In conclusion, β-glucans were able to modulate the immune system by promoting cell viability, phagocytic activity, antioxidant immune response and immune-related gene expression in leukocytes. Therefore, β-glucans derived from Debaryomyces hansenii should be considered a potential immunostimulant for goat production systems. Copyright © 2018 Elsevier B.V. All rights reserved.

How do plants achieve immunity? Defence without specialized immune cells.

PubMed

Spoel, Steven H; Dong, Xinnian

2012-01-25

Vertebrates have evolved a sophisticated adaptive immune system that relies on an almost infinite diversity of antigen receptors that are clonally expressed by specialized immune cells that roam the circulatory system. These immune cells provide vertebrates with extraordinary antigen-specific immune capacity and memory, while minimizing self-reactivity. Plants, however, lack specialized mobile immune cells. Instead, every plant cell is thought to be capable of launching an effective immune response. So how do plants achieve specific, self-tolerant immunity and establish immune memory? Recent developments point towards a multilayered plant innate immune system comprised of self-surveillance, systemic signalling and chromosomal changes that together establish effective immunity.

Dynamic network reconstruction from gene expression data applied to immune response during bacterial infection.

PubMed

Guthke, Reinhard; Möller, Ulrich; Hoffmann, Martin; Thies, Frank; Töpfer, Susanne

2005-04-15

The immune response to bacterial infection represents a complex network of dynamic gene and protein interactions. We present an optimized reverse engineering strategy aimed at a reconstruction of this kind of interaction networks. The proposed approach is based on both microarray data and available biological knowledge. The main kinetics of the immune response were identified by fuzzy clustering of gene expression profiles (time series). The number of clusters was optimized using various evaluation criteria. For each cluster a representative gene with a high fuzzy-membership was chosen in accordance with available physiological knowledge. Then hypothetical network structures were identified by seeking systems of ordinary differential equations, whose simulated kinetics could fit the gene expression profiles of the cluster-representative genes. For the construction of hypothetical network structures singular value decomposition (SVD) based methods and a newly introduced heuristic Network Generation Method here were compared. It turned out that the proposed novel method could find sparser networks and gave better fits to the experimental data. Reinhard.Guthke@hki-jena.de.

Mechanism of foreign DNA selection in a bacterial adaptive immune system

PubMed Central

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

2012-01-01

Summary 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 “non-self” 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 non-self 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 3-base pair motif that is required for non-self 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. PMID:22521690

Guide-bound structures of an RNA-targeting A-cleaving CRISPR-Cas13a enzyme

PubMed Central

Knott, Gavin J.; East-Seletsky, Alexandra; Cofsky, Joshua C.; Holton, James M.; Charles, Emeric; O’Connell, Mitchell R.; Doudna, Jennifer A.

2018-01-01

CRISPR adaptive immune systems protect bacteria from infections by deploying CRISPR RNA (crRNA)-guided enzymes to recognize and cut foreign nucleic acids. Type VI-A CRISPR-Cas systems include the Cas13a enzyme, an RNA-activated ribonuclease (RNase) capable of crRNA processing and single-stranded RNA degradation upon target transcript binding. Here we present the 2.0 Å resolution crystal structure of a crRNA-bound L. bacterium Cas13a (LbaCas13a), representing a recently discovered Cas13a enzyme subtype. This structure and accompanying biochemical experiments define for the first time the Cas13a catalytic residues that are directly responsible for crRNA maturation. In addition, the orientation of the foreign-derived target RNA-specifying sequence in the protein interior explains the conformational gating of Cas13a nuclease activation. These results describe how Cas13a enzymes generate functional crRNAs and how catalytic activity is blocked prior to target RNA recognition, with implications for both bacterial immunity and diagnostic applications. PMID:28892041

The ecology of immune state in a wild mammal, Mus musculus domesticus.

PubMed

Abolins, Stephen; Lazarou, Luke; Weldon, Laura; Hughes, Louise; King, Elizabeth C; Drescher, Paul; Pocock, Michael J O; Hafalla, Julius C R; Riley, Eleanor M; Viney, Mark

2018-04-01

The immune state of wild animals is largely unknown. Knowing this and what affects it is important in understanding how infection and disease affects wild animals. The immune state of wild animals is also important in understanding the biology of their pathogens, which is directly relevant to explaining pathogen spillover among species, including to humans. The paucity of knowledge about wild animals' immune state is in stark contrast to our exquisitely detailed understanding of the immunobiology of laboratory animals. Making an immune response is costly, and many factors (such as age, sex, infection status, and body condition) have individually been shown to constrain or promote immune responses. But, whether or not these factors affect immune responses and immune state in wild animals, their relative importance, and how they interact (or do not) are unknown. Here, we have investigated the immune ecology of wild house mice-the same species as the laboratory mouse-as an example of a wild mammal, characterising their adaptive humoral, adaptive cellular, and innate immune state. Firstly, we show how immune variation is structured among mouse populations, finding that there can be extensive immune discordance among neighbouring populations. Secondly, we identify the principal factors that underlie the immunological differences among mice, showing that body condition promotes and age constrains individuals' immune state, while factors such as microparasite infection and season are comparatively unimportant. By applying a multifactorial analysis to an immune system-wide analysis, our results bring a new and unified understanding of the immunobiology of a wild mammal.

NMR resonance assignments of the lantibiotic immunity protein NisI from Lactococcus lactis.

PubMed

Hacker, Carolin; Christ, Nina Alexandra; Duchardt-Ferner, Elke; Korn, Sophie; Berninger, Lucija; Kötter, Peter; Entian, Karl-Dieter; Wöhnert, Jens

2015-10-01

The lantibiotic nisin is a small antimicrobial peptide which acts against a wide range of Gram-positive bacteria. Nisin-producing Lactococcus lactis strains express four genes for self-protection against their own antimicrobial compound. This immunity system consists of the lipoprotein NisI and the ABC transporter NisFEG. NisI is attached to the outside of the cytoplasmic membrane via a covalently linked diacylglycerol anchor. Both the lipoprotein and the ABC transporter are needed for full immunity but the exact immunity mechanism is still unclear. To gain insights into the highly specific immunity mechanism of nisin producing strains on a structural level we present here the backbone resonance assignment of NisI (25.8 kDa) as well as the virtually complete (1)H,(15)N,(13)C chemical shift assignments for the isolated 12.7 kDa N-terminal and 14.6 kDa C-terminal domains of NisI.

Dendritic cell targeted vaccines: Recent progresses and challenges

PubMed Central

Chen, Pengfei; Liu, Xinsheng; Sun, Yuefeng; Zhou, Peng; Wang, Yonglu; Zhang, Yongguang

2016-01-01

ABSTRACT Dendritic cells (DCs) are known to be a set of morphology, structure and function of heterogeneous professional antigen presenting cells (APCs), as well as the strongest functional antigen presenting cells, which can absorb, process and present antigens. As the key regulators of innate and adaptive immune responses, DCs are at the center of the immune system and capable of interacting with both B cells and T cells, thereby manipulating the humoral and cellular immune responses. DCs provide an essential link between the innate and adaptive immunity, and the strong immune activation function of DCs and their properties of natural adjuvants, make them a valuable target for antigen delivery. Targeting antigens to DC-specific endocytic receptors in combination with the relevant antibodies or ligands along with immunostimulatory adjuvants has been recently recognized as a promising strategy for designing an effective vaccine that elicits a strong and durable T cell response against intracellular pathogens and cancer. This opinion article provides a brief summary of the rationales, superiorities and challenges of existing DC-targeting approaches. PMID:26513200

Crystal Structure of Marburg Virus VP40 Reveals a Broad, Basic Patch for Matrix Assembly and a Requirement of the N-Terminal Domain for Immunosuppression.

PubMed

Oda, Shun-Ichiro; Noda, Takeshi; Wijesinghe, Kaveesha J; Halfmann, Peter; Bornholdt, Zachary A; Abelson, Dafna M; Armbrust, Tammy; Stahelin, Robert V; Kawaoka, Yoshihiro; Saphire, Erica Ollmann

2016-02-15

Marburg virus (MARV), a member of the filovirus family, causes severe hemorrhagic fever with up to 90% lethality. MARV matrix protein VP40 is essential for assembly and release of newly copied viruses and also suppresses immune signaling in the infected cell. Here we report the crystal structure of MARV VP40. We found that MARV VP40 forms a dimer in solution, mediated by N-terminal domains, and that formation of this dimer is essential for budding of virus-like particles. We also found the N-terminal domain to be necessary and sufficient for immune antagonism. The C-terminal domains of MARV VP40 are dispensable for immunosuppression but are required for virus assembly. The C-terminal domains are only 16% identical to those of Ebola virus, differ in structure from those of Ebola virus, and form a distinct broad and flat cationic surface that likely interacts with the cell membrane during virus assembly. Marburg virus, a cousin of Ebola virus, causes severe hemorrhagic fever, with up to 90% lethality seen in recent outbreaks. Molecular structures and visual images of the proteins of Marburg virus are essential for the development of antiviral drugs. One key protein in the Marburg virus life cycle is VP40, which both assembles the virus and suppresses the immune system. Here we provide the molecular structure of Marburg virus VP40, illustrate differences from VP40 of Ebola virus, and reveal surfaces by which Marburg VP40 assembles progeny and suppresses immune function. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Tianyu; University of Chinese Academy of Sciences, Beijing 100049; Ding, Jinjing

The structure of the Tse3–Tsi3 complex associated with the bacterial type VI secretion system of P. aeruginosa has been solved and refined at 1.9 Å resolution. The structural basis of the recognition of the muramidase effector and its inactivation by its cognate immunity protein is revealed. The type VI secretion system (T6SS) is a bacterial protein-export machine that is capable of delivering virulence effectors between Gram-negative bacteria. The T6SS of Pseudomonas aeruginosa transports two lytic enzymes, Tse1 and Tse3, to degrade cell-wall peptidoglycan in the periplasm of rival bacteria that are competing for niches via amidase and muramidase activities, respectively.more » Two cognate immunity proteins, Tsi1 and Tsi3, are produced by the bacterium to inactivate the two antibacterial effectors, thereby protecting its siblings from self-intoxication. Recently, Tse1–Tsi1 has been structurally characterized. Here, the structure of the Tse3–Tsi3 complex is reported at 1.9 Å resolution. The results reveal that Tse3 contains a C-terminal catalytic domain that adopts a soluble lytic transglycosylase (SLT) fold in which three calcium-binding sites were surprisingly observed close to the catalytic Glu residue. The electrostatic properties of the substrate-binding groove are also distinctive from those of known structures with a similar fold. All of these features imply that a unique catalytic mechanism is utilized by Tse3 in cleaving glycosidic bonds. Tsi3 comprises a single domain showing a β-sandwich architecture that is reminiscent of the immunoglobulin fold. Three loops of Tsi3 insert deeply into the groove of Tse3 and completely occlude its active site, which forms the structural basis of Tse3 inactivation. This work is the first crystallographic report describing the three-dimensional structure of the Tse3–Tsi3 effector–immunity pair.« less

Crystal structure of a shark single-domain antibody V region in complex with lysozyme.

PubMed

Stanfield, Robyn L; Dooley, Helen; Flajnik, Martin F; Wilson, Ian A

2004-09-17

Cartilaginous fish are the phylogenetically oldest living organisms known to possess components of the vertebrate adaptive immune system. Key to their immune response are heavy-chain, homodimeric immunoglobulins called new antigen receptors (IgNARs), in which the variable (V) domains recognize antigens with only a single immunoglobulin domain, akin to camelid heavy-chain V domains. The 1.45 angstrom resolution crystal structure of the type I IgNAR V domain in complex with hen egg-white lysozyme (HEL) reveals a minimal antigen-binding domain that contains only two of the three conventional complementarity-determining regions but still binds HEL with nanomolar affinity by means of a binding interface comparable in size to conventional antibodies.

Dysfunctions of the Iga system: a common link between intestinal and renal diseases

PubMed Central

Papista, Christina; Berthelot, Laureline; Monteiro, Renato C

2011-01-01

Immunoglobulin A (Iga)-isotype antibodies play an important role in immunity owing to their structure, glycosylation, localization and receptor interactions. Dysfunctions in this system can lead to multiple types of pathology. This review describes the characteristics of Iga and discusses the involvement of abnormalities in the Iga system on the development of celiac disease and Iga nephropathy. PMID:21278767

Systemic Sclerosis and the Gastrointestinal Tract-Clinical Approach.

PubMed

Braun-Moscovici, Yolanda; Brun, Rita; Braun, Marius

2016-10-31

Systemic sclerosis (SSc) is a multisystem disease characterized by functional and structural abnormalities of small blood vessels, fibrosis of the skin and internal organs, immune system activation, and autoimmunity. The gastrointestinal tract is involved in nearly all patients and is a source of significant morbidity and even mortality. The aim of this review is to summarize the pathogenesis and to provide a clinical approach to these patients.

Virus-like nanostructures for tuning immune response

NASA Astrophysics Data System (ADS)

Mammadov, Rashad; Cinar, Goksu; Gunduz, Nuray; Goktas, Melis; Kayhan, Handan; Tohumeken, Sehmus; Topal, Ahmet E.; Orujalipoor, Ilghar; Delibasi, Tuncay; Dana, Aykutlu; Ide, Semra; Tekinay, Ayse B.; Guler, Mustafa O.

2015-11-01

Synthetic vaccines utilize viral signatures to trigger immune responses. Although the immune responses raised against the biochemical signatures of viruses are well characterized, the mechanism of how they affect immune response in the context of physical signatures is not well studied. In this work, we investigated the ability of zero- and one-dimensional self-assembled peptide nanostructures carrying unmethylated CpG motifs (signature of viral DNA) for tuning immune response. These nanostructures represent the two most common viral shapes, spheres and rods. The nanofibrous structures were found to direct immune response towards Th1 phenotype, which is responsible for acting against intracellular pathogens such as viruses, to a greater extent than nanospheres and CpG ODN alone. In addition, nanofibers exhibited enhanced uptake into dendritic cells compared to nanospheres or the ODN itself. The chemical stability of the ODN against nuclease-mediated degradation was also observed to be enhanced when complexed with the peptide nanostructures. In vivo studies showed that nanofibers promoted antigen-specific IgG production over 10-fold better than CpG ODN alone. To the best of our knowledge, this is the first report showing the modulation of the nature of an immune response through the shape of the carrier system.

Neuron-directed autoimmunity in the central nervous system: entities, mechanisms, diagnostic clues, and therapeutic options.

PubMed

Melzer, Nico; Meuth, Sven G; Wiendl, Heinz

2012-06-01

The human central nervous system (CNS) can mistakenly be the target of adaptive cellular and humoral immune responses causing both functional and structural impairment. We here provide an overview of neuron-directed autoimmunity as a novel class of inflammatory CNS disorders, their differential diagnoses, clinical hallmarks, imaging features, characteristic laboratory, electrophysiological, cerebrospinal fluid and neuropathological findings, cellular and molecular disease mechanisms, as well as therapeutic options. A growing number of immune-mediated CNS disorders of both autoimmune and paraneoplastic origin have emerged, in which neurons seem to be the target of the immune response. Antibodies binding to a variety of synaptic and extrasynaptic antigens located on the neuronal surface membrane can define distinct entities. Clinically, these disorders are characterized by subacute CNS-related [and sometimes peripheral nervous system (PNS)-related] symptoms involving a variety of cortical and subcortical gray matter areas, which often reflect the expression pattern and function of the respective target antigen. Antibodies seem to be pathogenic and cause (reversible) disturbance of synaptic transmission and neuronal excitability by selective functional inhibition or crosslinking and internalization of their antigen in the absence of overt cytotoxicity, at least at early disease stages. Whether at later disease stages antibody-mediated cytotoxicity, cytotoxic CD8+ T cells, or other detrimental immune mechanisms contribute to neuronal impairment is unclear at present. Adaptive humoral autoimmunity directed to neuronal cell-surface antigens offers first and unique insights and provokes further investigation into the systemic, cellular, and molecular consequences of immune-mediated disruption of distinct neuronal signaling pathways within the living human CNS.

High Molecular Weight Isoforms of Growth Hormone In Cells of the Immune System

PubMed Central

Weigent, Douglas A.

2013-01-01

A substantial body of research exists to support the idea that cells of the immune system produce growth hormone (GH). However, the structure and mechanism of action of lymphocyte-derived GH continues to remain largely unknown. Here we present the results of Western analysis of whole cell extracts showing that different molecular weight isoforms of GH of approximately 100 kDa, 65 kDa, and 48 kDa can be detected in primary mouse cells of the immune system and in the mouse EL4 cell line. The identity of the 65 kDa and 48 kDa isoforms of GH were confirmed by mass spectrometry. The various isoforms were detected in both enriched T and B spleen cell populations. The large molecular weight isoform appears to reside primarily in the cytoplasm whereas the lower molecular weight 65 kDa and 48 kDa isoforms were detected primarily in the nucleus. These results also suggest that GH isoforms are induced by oxidative stress. In EL4 cells overexpressing GH, the expression of luciferase controlled by a promoter containing the antioxidant response element is increased almost three-fold above control. The data suggest that the induction of isoforms of the GH molecule in cells of the immune system may be an important mechanism of adaptation and/or protection of lymphoid cells under conditions of oxidative stress. PMID:21741628

Artificial immune algorithm for multi-depot vehicle scheduling problems

NASA Astrophysics Data System (ADS)

Wu, Zhongyi; Wang, Donggen; Xia, Linyuan; Chen, Xiaoling

2008-10-01

In the fast-developing logistics and supply chain management fields, one of the key problems in the decision support system is that how to arrange, for a lot of customers and suppliers, the supplier-to-customer assignment and produce a detailed supply schedule under a set of constraints. Solutions to the multi-depot vehicle scheduling problems (MDVRP) help in solving this problem in case of transportation applications. The objective of the MDVSP is to minimize the total distance covered by all vehicles, which can be considered as delivery costs or time consumption. The MDVSP is one of nondeterministic polynomial-time hard (NP-hard) problem which cannot be solved to optimality within polynomial bounded computational time. Many different approaches have been developed to tackle MDVSP, such as exact algorithm (EA), one-stage approach (OSA), two-phase heuristic method (TPHM), tabu search algorithm (TSA), genetic algorithm (GA) and hierarchical multiplex structure (HIMS). Most of the methods mentioned above are time consuming and have high risk to result in local optimum. In this paper, a new search algorithm is proposed to solve MDVSP based on Artificial Immune Systems (AIS), which are inspirited by vertebrate immune systems. The proposed AIS algorithm is tested with 30 customers and 6 vehicles located in 3 depots. Experimental results show that the artificial immune system algorithm is an effective and efficient method for solving MDVSP problems.

The twilight of immunity: emerging concepts in aging of the immune system.

PubMed

Nikolich-Žugich, Janko

2018-01-01

Immunosenescence is a series of age-related changes that affect the immune system and, with time, lead to increased vulnerability to infectious diseases. This Review addresses recent developments in the understanding of age-related changes that affect key components of immunity, including the effect of aging on cells of the (mostly adaptive) immune system, on soluble molecules that guide the maintenance and function of the immune system and on lymphoid organs that coordinate both the maintenance of lymphocytes and the initiation of immune responses. I further address the effect of the metagenome and exposome as key modifiers of immune-system aging and discuss a conceptual framework in which age-related changes in immunity might also affect the basic rules by which the immune system operates.

Autoimmune Thyroiditis and Myasthenia Gravis

PubMed Central

Lopomo, Angela; Berrih-Aknin, Sonia

2017-01-01

Autoimmune diseases (AIDs) are the result of specific immune responses directed against structures of the self. In normal conditions, the molecules recognized as “self” are tolerated by immune system, but when the self-tolerance is lost, the immune system could react against molecules from the body, causing the loss of self-tolerance, and subsequently the onset of AID that differs for organ target and etiology. Autoimmune thyroid disease (ATD) is caused by the development of autoimmunity against thyroid antigens and comprises Hashimoto’s thyroiditis and Graves disease. They are frequently associated with other organ or non-organ specific AIDs, such as myasthenia gravis (MG). In fact, ATD seems to be the most associated pathology to MG. The etiology of both diseases is multifactorial and it is due to genetic and environmental factors, and each of them has specific characteristics. The two pathologies show many commonalities, such as the organ-specificity with a clear pathogenic effect of antibodies, the pathological mechanisms, such as deregulation of the immune system and the implication of the genetic predisposition. They also show some differences, such as the mode of action of the antibodies and therapies. In this review that focuses on ATD and MG, the common features and the differences between the two diseases are discussed. PMID:28751878

A Service Oriented Architecture Approach to Achieve Interoperability between Immunization Information Systems in Iran

PubMed Central

Hosseini, Masoud; Ahmadi, Maryam; Dixon, Brian E.

2014-01-01

Clinical decision support (CDS) systems can support vaccine forecasting and immunization reminders; however, immunization decision-making requires data from fragmented, independent systems. Interoperability and accurate data exchange between immunization information systems (IIS) is an essential factor to utilize Immunization CDS systems. Service oriented architecture (SOA) and Health Level 7 (HL7) are dominant standards for web-based exchange of clinical information. We implemented a system based on SOA and HL7 v3 to support immunization CDS in Iran. We evaluated system performance by exchanging 1500 immunization records for roughly 400 infants between two IISs. System turnaround time is less than a minute for synchronous operation calls and the retrieved immunization history of infants were always identical in different systems. CDS generated reports were accordant to immunization guidelines and the calculations for next visit times were accurate. Interoperability is rare or nonexistent between IIS. Since inter-state data exchange is rare in United States, this approach could be a good prototype to achieve interoperability of immunization information. PMID:25954452

A Service Oriented Architecture Approach to Achieve Interoperability between Immunization Information Systems in Iran.

PubMed

Hosseini, Masoud; Ahmadi, Maryam; Dixon, Brian E

2014-01-01

Clinical decision support (CDS) systems can support vaccine forecasting and immunization reminders; however, immunization decision-making requires data from fragmented, independent systems. Interoperability and accurate data exchange between immunization information systems (IIS) is an essential factor to utilize Immunization CDS systems. Service oriented architecture (SOA) and Health Level 7 (HL7) are dominant standards for web-based exchange of clinical information. We implemented a system based on SOA and HL7 v3 to support immunization CDS in Iran. We evaluated system performance by exchanging 1500 immunization records for roughly 400 infants between two IISs. System turnaround time is less than a minute for synchronous operation calls and the retrieved immunization history of infants were always identical in different systems. CDS generated reports were accordant to immunization guidelines and the calculations for next visit times were accurate. Interoperability is rare or nonexistent between IIS. Since inter-state data exchange is rare in United States, this approach could be a good prototype to achieve interoperability of immunization information.

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. Copyright 2010 Elsevier Ltd. All rights reserved.

The species recognition system: a new corollary for the human fetoembryonic defense system hypothesis.

PubMed

Clark, G F; Dell, A; Morris, H R; Patankar, M S; Easton, R L

2001-01-01

We have previously suggested that the human fetus is protected during human development by a system of both soluble and cell surface associated glycoconjugates that utilize their carbohydrate sequences as functional groups to enable them to evoke tolerance. The proposed model has been referred to as the human fetoembryonic defense system hypothesis (hu-FEDS). In this paradigm, it has previously been proposed that similar oligosaccharides are used to mediate crucial recognition events required during both human sperm-egg binding and immune-inflammatory cell interactions. This vertical integration suggested to us that the sperm-egg binding itself is related to universal recognition events that occur between immune and inflammatory cells, except that in this case recognition of 'species' rather than recognition of 'self' is being manifested. In this paper, we have designated this component of hu-FEDS as the species recognition system (SRS). We propose that the SRS is an integral component of the hu-FEDS used to enable sperm-egg recognition and protection of the gametes from potential immune responses. Recent structural data indicates that the glycan sequences implicated in mediating murine gamete recognition are also expressed on CD45 in activated murine T lymphocytes and cytotoxic T lymphocytes. This overlap supports our contention that there is an overlap between the immune and gamete recognition systems. Therefore the hu-FEDS paradigm may be a subset of a larger model that also applies to other placental mammals. We therefore propose that the hu-FEDS model for protection should in the future be referred to as the eutherian fetoembryonic defense system hypothesis (eu-FEDS) to account for this extension. The possibility exists that the SRS component of eu-FEDS could predate eutherians and extend to all sexually reproducing organisms. Future investigation of the interactions between the immune and gamete recognition system will be required to determine the degree of overlap. Copyright 2001 S. Karger AG, Basel

[Specific features of blood cell composition and structure in fishes from the pelagial and coastal zones of Lake Baikal].

PubMed

Iakhnenko, V M; Klimenkov, I V

2009-01-01

Differences in the proportions and ultrastructure of peripheral blood cells between the Baikal cisco and roach have been revealed. Both species contain all main cell types involved in the immune response in higher vertebrates. However, cells mediating the innate immune response are represented in the Baikal cisco only by monocytes and pseudogranulocytes, whereas the blood of roach additionally contains true granulocytes. Significantly greater numbers of leukocytes and thrombocytes per unit volume in the roach are evidence for mobilization of the immune system in this species. The peripheral blood of both species contains lymphocytes, which are responsible for adaptive immunity. The content of hemoglobin in erythrocytes is lower in the roach than in the Baikal cisco. The state of blood in the two species may be considered adapted to typical conditions in their habitats.

The Immune System: Basis of so much Health and Disease: 4. Immunocytes.

PubMed

Scully, Crispian; Georgakopoulou, Eleni A; Hassona, Yazan

2017-05-01

The immune system is the body’s primary defence mechanism against infections, and disturbances in the system can cause disease if the system fails in defence functions (in immunocompromised people), or if the activity is detrimental to the host (as in auto-immune and auto-inflammatory states). A healthy immune system is also essential to normal health of dental and oral tissues. This series presents the basics for the understanding of the immune system, this article covers cells of the immune system (immunocytes). Clinical relevance: Modern dental clinicians need a basic understanding of the immune system as it underlies health and disease.

Intestinal barrier: A gentlemen’s agreement between microbiota and immunity

PubMed Central

Caricilli, Andrea Moro; Castoldi, Angela; Câmara, Niels Olsen Saraiva

2014-01-01

Our body is colonized by more than a hundred trillion commensals, represented by viruses, bacteria and fungi. This complex interaction has shown that the microbiome system contributes to the host’s adaptation to its environment, providing genes and functionality that give flexibility of diet and modulate the immune system in order not to reject these symbionts. In the intestine, specifically, the microbiota helps developing organ structures, participates of the metabolism of nutrients and induces immunity. Certain components of the microbiota have been shown to trigger inflammatory responses, whereas others, anti-inflammatory responses. The diversity and the composition of the microbiota, thus, play a key role in the maintenance of intestinal homeostasis and explain partially the link between intestinal microbiota changes and gut-related disorders in humans. Tight junction proteins are key molecules for determination of the paracellular permeability. In the context of intestinal inflammatory diseases, the intestinal barrier is compromised, and decreased expression and differential distribution of tight junction proteins is observed. It is still unclear what is the nature of the luminal or mucosal factors that affect the tight junction proteins function, but the modulation of the immune cells found in the intestinal lamina propria is hypothesized as having a role in this modulation. In this review, we provide an overview of the current understanding of the interaction of the gut microbiota with the immune system in the development and maintenance of the intestinal barrier. PMID:24891972

Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa.

PubMed

Dantzer, Robert

2018-01-01

Because of the compartmentalization of disciplines that shaped the academic landscape of biology and biomedical sciences in the past, physiological systems have long been studied in isolation from each other. This has particularly been the case for the immune system. As a consequence of its ties with pathology and microbiology, immunology as a discipline has largely grown independently of physiology. Accordingly, it has taken a long time for immunologists to accept the concept that the immune system is not self-regulated but functions in close association with the nervous system. These associations are present at different levels of organization. At the local level, there is clear evidence for the production and use of immune factors by the central nervous system and for the production and use of neuroendocrine mediators by the immune system. Short-range interactions between immune cells and peripheral nerve endings innervating immune organs allow the immune system to recruit local neuronal elements for fine tuning of the immune response. Reciprocally, immune cells and mediators play a regulatory role in the nervous system and participate in the elimination and plasticity of synapses during development as well as in synaptic plasticity at adulthood. At the whole organism level, long-range interactions between immune cells and the central nervous system allow the immune system to engage the rest of the body in the fight against infection from pathogenic microorganisms and permit the nervous system to regulate immune functioning. Alterations in communication pathways between the immune system and the nervous system can account for many pathological conditions that were initially attributed to strict organ dysfunction. This applies in particular to psychiatric disorders and several immune-mediated diseases. This review will show how our understanding of this balance between long-range and short-range interactions between the immune system and the central nervous system has evolved over time, since the first demonstrations of immune influences on brain functions. The necessary complementarity of these two modes of communication will then be discussed. Finally, a few examples will illustrate how dysfunction in these communication pathways results in what was formerly considered in psychiatry and immunology to be strict organ pathologies.

Autoantigens in systemic autoimmunity: critical partner in pathogenesis

PubMed Central

Rosen, A.; Casciola-Rosen, L.

2013-01-01

Understanding the mechanisms of human autoimmune rheumatic diseases presents a major challenge, due to marked complexity involving multiple domains, including genetics, environment and kinetics. In spite of this, the immune response in each of these diseases is largely specific, with distinct autoantibodies associated with different disease phenotypes. Defining the basis of such specificity will provide important insights into disease mechanism. Accumulating data suggest an interesting paradigm for antigen selection in autoimmunity, in which target tissue and immune effector pathways form a mutually reinforcing partnership. In this model, distinct autoantibody patterns in autoimmunity may be viewed as the integrated, amplified output of several interacting systems, including: (i) the specific target tissue, (ii) the immune effector pathways that modify antigen structure and cause tissue damage and dysfunction, and (iii) the homeostatic pathways activated in response to damage (e.g. regeneration/differentiation/cytokine effects). As unique antigen expression and structure may occur exclusively under these amplifying circumstances, it is useful to view the molecules targeted as ‘neo-antigens’, that is, antigens expressed under specific conditions, rather than ubiquitously. This model adds an important new dynamic element to selection of antigen targets in autoimmunity, and suggests that the amplifying loop will only be identified by studying the diseased target tissue in vivo. PMID:19493056

Maiden immunization coverage survey in the republic of South Sudan: a cross-sectional study providing baselines for future performance measurement.

PubMed

Mbabazi, William; Lako, Anthony K; Ngemera, Daniel; Laku, Richard; Yehia, Mostafah; Nshakira, Nathan

2013-01-01

Since the comprehensive peace agreement was signed in 2005, institutionalization of immunization services in South Sudan remained a priority. Routine administrative reporting systems were established and showed that national coverage rates for DTP-3 rose from 20% in 2002 to 80% in 2011. This survey was conducted as part of an overall review of progress in implementation of the first EPI Multi-Year Plan for South Sudan 2007-2011. This report provides maiden community coverage estimates for immunization. A cross sectional community survey was conducted between January and May 2012. Ten cluster surveys were conducted to generate state-specific coverage estimates. The WHO 30x7 cluster sampling method was employed. Data was collected using pre-tested, interviewer guided, structured questionnaires through house to house visits. The fully immunized children were 7.3%. Coverage for specific antigens were; BCG (28.3%), DTP-1(25.9%), DTP-3 (22.0%), Measles (16.8%). The drop-out rate between the first and third doses of DTP was 21.3%. Immunization coverage estimates based on card and history were higher, at 45.7% for DTP-3, 45.8% for MCV and 32.2% for full immunization. Majority of immunizations (80.8%) were received at health facilities compared to community service points (19.2%). The major reason for missed immunizations was inadequate information (41.1%). The proportion of card-verified, fully vaccinated among children aged 12-23 months is very low at 7.3%. Future efforts to improve vaccination quality and coverage should prioritize training of vaccinators and program communication to levels equivalent or higher than investments in EPI cold chain systems since 2007.

Maiden immunization coverage survey in the republic of South Sudan: a cross-sectional study providing baselines for future performance measurement

PubMed Central

Mbabazi, William; Lako, Anthony K; Ngemera, Daniel; Laku, Richard; Yehia, Mostafah; Nshakira, Nathan

2013-01-01

Introduction Since the comprehensive peace agreement was signed in 2005, institutionalization of immunization services in South Sudan remained a priority. Routine administrative reporting systems were established and showed that national coverage rates for DTP-3 rose from 20% in 2002 to 80% in 2011. This survey was conducted as part of an overall review of progress in implementation of the first EPI Multi-Year Plan for South Sudan 2007-2011. This report provides maiden community coverage estimates for immunization. Methods A cross sectional community survey was conducted between January and May 2012. Ten cluster surveys were conducted to generate state-specific coverage estimates. The WHO 30x7 cluster sampling method was employed. Data was collected using pre-tested, interviewer guided, structured questionnaires through house to house visits. Results The fully immunized children were 7.3%. Coverage for specific antigens were; BCG (28.3%), DTP-1(25.9%), DTP-3 (22.0%), Measles (16.8%). The drop-out rate between the first and third doses of DTP was 21.3%. Immunization coverage estimates based on card and history were higher, at 45.7% for DTP-3, 45.8% for MCV and 32.2% for full immunization. Majority of immunizations (80.8%) were received at health facilities compared to community service points (19.2%). The major reason for missed immunizations was inadequate information (41.1%). Conclusion The proportion of card-verified, fully vaccinated among children aged 12-23 months is very low at 7.3%. Future efforts to improve vaccination quality and coverage should prioritize training of vaccinators and program communication to levels equivalent or higher than investments in EPI cold chain systems since 2007. PMID:24876899

Evaluation of Mucosal and Systemic Immune Responses Elicited by GPI-0100- Adjuvanted Influenza Vaccine Delivered by Different Immunization Strategies

PubMed Central

Liu, Heng; Patil, Harshad P.; de Vries-Idema, Jacqueline; Wilschut, Jan; Huckriede, Anke

2013-01-01

Vaccines for protection against respiratory infections should optimally induce a mucosal immune response in the respiratory tract in addition to a systemic immune response. However, current parenteral immunization modalities generally fail to induce mucosal immunity, while mucosal vaccine delivery often results in poor systemic immunity. In order to find an immunization strategy which satisfies the need for induction of both mucosal and systemic immunity, we compared local and systemic immune responses elicited by two mucosal immunizations, given either by the intranasal (IN) or the intrapulmonary (IPL) route, with responses elicited by a mucosal prime followed by a systemic boost immunization. The study was conducted in BALB/c mice and the vaccine formulation was an influenza subunit vaccine supplemented with GPI-0100, a saponin-derived adjuvant. While optimal mucosal antibody titers were obtained after two intrapulmonary vaccinations, optimal systemic antibody responses were achieved by intranasal prime followed by intramuscular boost. The latter strategy also resulted in the best T cell response, yet, it was ineffective in inducing nose or lung IgA. Successful induction of secretory IgA, IgG and T cell responses was only achieved with prime-boost strategies involving intrapulmonary immunization and was optimal when both immunizations were given via the intrapulmonary route. Our results underline that immunization via the lungs is particularly effective for priming as well as boosting of local and systemic immune responses. PMID:23936066

Systems vaccinology: Probing humanity’s diverse immune systems with vaccines

PubMed Central

Pulendran, Bali

2014-01-01

Homo sapiens are genetically diverse, but dramatic demographic and socioeconomic changes during the past century have created further diversification with respect to age, nutritional status, and the incidence of associated chronic inflammatory disorders and chronic infections. These shifting demographics pose new challenges for vaccination, as emerging evidence suggests that age, the metabolic state, and chronic infections can exert major influences on the immune system. Thus, a key public health challenge is learning how to reprogram suboptimal immune systems to induce effective vaccine immunity. Recent advances have applied systems biological analysis to define molecular signatures induced early after vaccination that correlate with and predict the later adaptive immune responses in humans. Such “systems vaccinology” approaches offer an integrated picture of the molecular networks driving vaccine immunity, and are beginning to yield novel insights about the immune system. Here we discuss the promise of systems vaccinology in probing humanity’s diverse immune systems, and in delineating the impact of genes, the environment, and the microbiome on protective immunity induced by vaccination. Such insights will be critical in reengineering suboptimal immune systems in immunocompromised populations. PMID:25136102

Systems vaccinology: probing humanity's diverse immune systems with vaccines.

PubMed

Pulendran, Bali

2014-08-26

Homo sapiens are genetically diverse, but dramatic demographic and socioeconomic changes during the past century have created further diversification with respect to age, nutritional status, and the incidence of associated chronic inflammatory disorders and chronic infections. These shifting demographics pose new challenges for vaccination, as emerging evidence suggests that age, the metabolic state, and chronic infections can exert major influences on the immune system. Thus, a key public health challenge is learning how to reprogram suboptimal immune systems to induce effective vaccine immunity. Recent advances have applied systems biological analysis to define molecular signatures induced early after vaccination that correlate with and predict the later adaptive immune responses in humans. Such "systems vaccinology" approaches offer an integrated picture of the molecular networks driving vaccine immunity, and are beginning to yield novel insights about the immune system. Here we discuss the promise of systems vaccinology in probing humanity's diverse immune systems, and in delineating the impact of genes, the environment, and the microbiome on protective immunity induced by vaccination. Such insights will be critical in reengineering suboptimal immune systems in immunocompromised populations.

Mucosal Vaccination Overcomes the Barrier to Recombinant Vaccinia Immunization Caused by Preexisting Poxvirus Immunity

NASA Astrophysics Data System (ADS)

Belyakov, Igor M.; Moss, Bernard; Strober, Warren; Berzofsky, Jay A.

1999-04-01

Overcoming preexisting immunity to vaccinia virus in the adult population is a key requirement for development of otherwise potent recombinant vaccinia vaccines. Based on our observation that s.c. immunization with vaccinia induces cellular and antibody immunity to vaccinia only in systemic lymphoid tissue and not in mucosal sites, we hypothesized that the mucosal immune system remains naive to vaccinia and therefore amenable to immunization with recombinant vaccinia vectors despite earlier vaccinia exposure. We show that mucosal immunization of vaccinia-immune BALB/c mice with recombinant vaccinia expressing HIV gp160 induced specific serum antibody and strong HIV-specific cytotoxic T lymphocyte responses. These responses occurred not only in mucosal but also in systemic lymphoid tissue, whereas systemic immunization was ineffective under these circumstances. In this context, intrarectal immunization was more effective than intranasal immunization. Boosting with a second dose of recombinant vaccinia was also more effective via the mucosal route. The systemic HIV-specific cytotoxic T lymphocyte response was enhanced by coadministration of IL-12 at the mucosal site. These results also demonstrate the independent compartmentalization of the mucosal versus systemic immune systems and the asymmetric trafficking of lymphocytes between them. This approach to circumvent previous vaccinia immunity may be useful for induction of protective immunity against infectious diseases and cancer in the sizable populations with preexisting immunity to vaccinia from smallpox vaccination.

Creating an arsenal of Adeno-associated virus (AAV) gene delivery stealth vehicles.

PubMed

Smith, J Kennon; Agbandje-McKenna, Mavis

2018-05-01

The Adeno-associated virus (AAV) gene delivery system is ushering in a new and exciting era in the United States; following the first approved gene therapy (Glybera) in Europe, the FDA has approved a second therapy, Luxturna [1]. However, challenges to this system remain. In viral gene therapy, the surface of the capsid is an important determinant of tissue tropism, impacts gene transfer efficiency, and is targeted by the human immune system. Preexisting immunity is a significant challenge to this approach, and the ability to visualize areas of antibody binding ("footprints") can inform efforts to improve the efficacy of viral vectors. Atomic resolution, smaller proteins, and asymmetric structures are the goals to attain in cryo-electron microscopy and image reconstruction (cryo-EM) as of late. The versatility of the technique and the ability to vitrify a wide range of heterogeneous molecules in solution allow structural biologists to characterize a variety of protein-DNA and protein-protein interactions at lower resolution. Cryo-EM has served as an important means to study key surface areas of the AAV gene delivery vehicle-specifically, those involved with binding neutralizing antibodies (NAbs) [2-4]. This method offers a unique opportunity for visualizing antibody binding "hotspots" on the surface of these and other viral vectors. When combined with mutagenesis, one can eliminate these hotspots to create viral vectors with the ability to avoid preexisting host immune recognition during gene delivery and genetic defect correction in disease treatment. Here, we discuss the use of structure-guided site-directed mutagenesis and directed evolution to create "stealth" AAV vectors with modified surface amino acid sequences that allow NAb avoidance while maintaining natural capsid functions or gaining desired novel tropisms.

Creating an arsenal of Adeno-associated virus (AAV) gene delivery stealth vehicles

PubMed Central

Agbandje-McKenna, Mavis

2018-01-01

The Adeno-associated virus (AAV) gene delivery system is ushering in a new and exciting era in the United States; following the first approved gene therapy (Glybera) in Europe, the FDA has approved a second therapy, Luxturna [1]. However, challenges to this system remain. In viral gene therapy, the surface of the capsid is an important determinant of tissue tropism, impacts gene transfer efficiency, and is targeted by the human immune system. Preexisting immunity is a significant challenge to this approach, and the ability to visualize areas of antibody binding (“footprints”) can inform efforts to improve the efficacy of viral vectors. Atomic resolution, smaller proteins, and asymmetric structures are the goals to attain in cryo-electron microscopy and image reconstruction (cryo-EM) as of late. The versatility of the technique and the ability to vitrify a wide range of heterogeneous molecules in solution allow structural biologists to characterize a variety of protein–DNA and protein–protein interactions at lower resolution. Cryo-EM has served as an important means to study key surface areas of the AAV gene delivery vehicle—specifically, those involved with binding neutralizing antibodies (NAbs) [2–4]. This method offers a unique opportunity for visualizing antibody binding “hotspots” on the surface of these and other viral vectors. When combined with mutagenesis, one can eliminate these hotspots to create viral vectors with the ability to avoid preexisting host immune recognition during gene delivery and genetic defect correction in disease treatment. Here, we discuss the use of structure-guided site-directed mutagenesis and directed evolution to create “stealth” AAV vectors with modified surface amino acid sequences that allow NAb avoidance while maintaining natural capsid functions or gaining desired novel tropisms. PMID:29723270

Conservation and variability in the structure and function of the Cas5d endoribonuclease in the CRISPR-mediated microbial immune system.

PubMed

Koo, Yoon; Ka, Donghyun; Kim, Eun-Jin; Suh, Nayoung; Bae, Euiyoung

2013-10-23

Clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins form an RNA-mediated microbial immune system against invading foreign genetic elements. Cas5 proteins constitute one of the most prevalent Cas protein families in CRISPR-Cas systems and are predicted to have RNA recognition motif (RRM) domains. Cas5d is a subtype I-C-specific Cas5 protein that can be divided into two distinct subgroups, one of which has extra C-terminal residues while the other contains a longer insertion in the middle of its N-terminal RRM domain. Here, we report crystal structures of Cas5d from Streptococcus pyogenes and Xanthomonas oryzae, which respectively represent the two Cas5d subgroups. Despite a common domain architecture consisting of an N-terminal RRM domain and a C-terminal β-sheet domain, the structural differences between the two Cas5d proteins are highlighted by the presence of a unique extended helical region protruding from the N-terminal RRM domain of X. oryzae Cas5d. We also demonstrate that Cas5d proteins possess not only specific endoribonuclease activity for CRISPR RNAs but also nonspecific double-stranded DNA binding affinity. These findings suggest that Cas5d may play multiple roles in CRISPR-mediated immunity. Furthermore, the specific RNA processing was also observed between S. pyogenes Cas5d protein and X. oryzae CRISPR RNA and vice versa. This cross-species activity of Cas5d provides a special opportunity for elucidating conserved features of the CRISPR RNA processing event. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Role of the Immune System Beyond the Fight Against Infection.

PubMed

Sattler, Susanne

2017-01-01

The immune system was identified as a protective factor during infectious diseases over a century ago. Current definitions and textbook information are still largely influenced by these early observations, and the immune system is commonly presented as a defence machinery. However, host defence is only one manifestation of the immune system's overall function in the maintenance of tissue homeostasis and system integrity. In fact, the immune system is integral part of fundamental physiological processes such as development, reproduction and wound healing, and a close crosstalk between the immune system and other body systems such as metabolism, the central nervous system and the cardiovascular system is evident. Research and medical professionals in an expanding range of areas start to recognise the implications of the immune system in their respective fields.This chapter provides a brief historical perspective on how our understanding of the immune system has evolved from a defence system to an overarching surveillance machinery to maintain tissue integrity. Current perspectives on the non-defence functions of classical immune cells and factors will also be discussed.

Plant Pathogenesis-Related Proteins PR-10 and PR-14 as Components of Innate Immunity System and Ubiquitous Allergens.

PubMed

Finkina, Ekaterina I; Melnikova, Daria N; Bogdanov, Ivan V; Ovchinnikova, Tatiana V

2017-01-01

Pathogenesis-related (PR) proteins are components of innate immunity system in plants. They play an important role in plant defense against pathogens. Lipid transfer proteins (LTPs) and Bet v 1 homologs comprise of two separate families of PR-proteins. Both LTPs (PR-14) and Bet v 1 homologs (PR-10) are multifunctional small proteins involving in plant response to abiotic and biotic stress conditions. The representatives of these PR-protein families do not show any sequence similarity but have other common biochemical features such as low molecular masses, the presence of hydrophobic cavities, ligand binding properties, and antimicrobial activities. Besides, many members of PR-10 and PR-14 families are ubiquitous plant panallergens which are able to cause sensitization of human immune system and crossreactive allergic reactions to plant food and pollen. This review is aimed at comparative analysis of structure-functional and allergenic properties of the PR-10 and PR-14 families, as well as prospects for their medicinal application. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Succeeding in New Vaccine Introduction: Lessons Learned From the Introduction of Inactivated Poliovirus Vaccine in Cameroon, Kenya, and Nigeria

PubMed Central

Snidal, Sarah; Saidu, Yauba; Ojumu, Abiola; Ngatia, Antony; Bagana, Murtala; Mutuku, Faith; Sobngwi, Joelle; Efe-Aluta, Oniovo; Roper, Julia; LeTallec, Yann; Kang’ethe, Alice

2017-01-01

Abstract Introducing a new vaccine is a large-scale endeavor that can face many challenges, resulting in introduction delays and inefficiencies. The development of national task teams and tools, such as prelaunch trackers, for the introduction of new vaccines (hereafter, “new vaccine introductions” [NVIs]) can help countries implement robust project management systems, front-load critical preparatory activities, and ensure continuous communication around vaccine supply and financing. In addition, implementing postlaunch assessments to take rapid corrective action accelerates the uptake of the new vaccines. NVIs can provide an opportunity to strengthen routine immunization, through strengthening program management systems or by reinforcing local immunization managers’ abilities, among others. This article highlights key lessons learned during the introduction of inactivated poliovirus vaccine in 3 countries that would make future NVIs more successful. The article concludes by considering how the Immunization Systems Management Group of the Global Polio Eradication Initiative has been useful to the NVI process and how such global structures could be further enhanced. PMID:28838156

Development of Quantitative Proteomics Using iTRAQ Based on the Immunological Response of Galleria mellonella Larvae Challenged with Fusarium oxysporum Microconidia

PubMed Central

Muñoz-Gómez, Amalia; Corredor, Mauricio; Benítez-Páez, Alfonso; Peláez, Carlos

2014-01-01

Galleria mellonella has emerged as a potential invertebrate model for scrutinizing innate immunity. Larvae are easy to handle in host-pathogen assays. We undertook proteomics research in order to understand immune response in a heterologous host when challenged with microconidia of Fusarium oxysporum. The aim of this study was to investigate hemolymph proteins that were differentially expressed between control and immunized larvae sets, tested with F. oxysporum at two temperatures. The iTRAQ approach allowed us to observe the effects of immune challenges in a lucid and robust manner, identifying more than 50 proteins, 17 of them probably involved in the immune response. Changes in protein expression were statistically significant, especially when temperature was increased because this was notoriously affected by F. oxysporum 104 or 106 microconidia/mL. Some proteins were up-regulated upon immune fungal microconidia challenge when temperature changed from 25 to 37°C. After analysis of identified proteins by bioinformatics and meta-analysis, results revealed that they were involved in transport, immune response, storage, oxide-reduction and catabolism: 20 from G. mellonella, 20 from the Lepidoptera species and 19 spread across bacteria, protista, fungi and animal species. Among these, 13 proteins and 2 peptides were examined for their immune expression, and the hypothetical 3D structures of 2 well-known proteins, unannotated for G. mellonella, i.e., actin and CREBP, were resolved using peptides matched with Bombyx mori and Danaus plexippus, respectively. The main conclusion in this study was that iTRAQ tool constitutes a consistent method to detect proteins associated with the innate immune system of G. mellonella in response to infection caused by F. oxysporum. In addition, iTRAQ was a reliable quantitative proteomic approach to detect and quantify the expression levels of immune system proteins and peptides, in particular, it was found that 104 microconidia/mL at 37°C over expressed many more proteins than other treatments. PMID:25379782

Combinatorial contextualization of peptidic epitopes for enhanced cellular immunity.

PubMed

Ito, Masaki; Hayashi, Kazumi; Adachi, Eru; Minamisawa, Tamiko; Homma, Sadamu; Koido, Shigeo; Shiba, Kiyotaka

2014-01-01

Invocation of cellular immunity by epitopic peptides remains largely dependent on empirically developed protocols, such as interfusion of aluminum salts or emulsification using terpenoids and surfactants. To explore novel vaccine formulation, epitopic peptide motifs were co-programmed with structural motifs to produce artificial antigens using our "motif-programming" approach. As a proof of concept, we used an ovalbumin (OVA) system and prepared an artificial protein library by combinatorially polymerizing MHC class I and II sequences from OVA along with a sequence that tends to form secondary structures. The purified endotoxin-free proteins were then examined for their ability to activate OVA-specific T-cell hybridoma cells after being processed within dendritic cells. One clone, F37A (containing three MHC I and two MHC II OVA epitopes), possessed a greater ability to evoke cellular immunity than the native OVA or the other artificial antigens. The sensitivity profiles of drugs that interfered with the F37A uptake differed from those of the other artificial proteins and OVA, suggesting that alteration of the cross-presentation pathway is responsible for the enhanced immunogenicity. Moreover, F37A, but not an epitopic peptide, invoked cellular immunity when injected together with monophosphoryl lipid A (MPL), and retarded tumor growth in mice. Thus, an artificially synthesized protein antigen induced cellular immunity in vivo in the absence of incomplete Freund's adjuvant or aluminum salts. The method described here could be potentially used for developing vaccines for such intractable ailments as AIDS, malaria and cancer, ailments in which cellular immunity likely play a crucial role in prevention and treatment.

Antibiotics modulate intestinal immunity and prevent necrotizing enterocolitis in preterm neonatal piglets

PubMed Central

Jensen, Michael L.; Thymann, Thomas; Cilieborg, Malene S.; Lykke, Mikkel; Mølbak, Lars; Jensen, Bent B.; Schmidt, Mette; Kelly, Denise; Mulder, Imke; Burrin, Douglas G.

2013-01-01

Preterm birth, bacterial colonization, and formula feeding predispose to necrotizing enterocolitis (NEC). Antibiotics are commonly administered to prevent sepsis in preterm infants, but it is not known whether this affects intestinal immunity and NEC resistance. We hypothesized that broad-spectrum antibiotic treatment improves NEC resistance and intestinal structure, function, and immunity in neonates. Caesarean-delivered preterm pigs were fed 3 days of parenteral nutrition followed by 2 days of enteral formula. Immediately after birth, they were assigned to receive either antibiotics (oral and parenteral doses of gentamycin, ampicillin, and metronidazole, ANTI, n = 11) or saline in the control group (CON, n = 13), given twice daily. NEC lesions and intestinal structure, function, microbiology, and immunity markers were recorded. None of the ANTI but 85% of the CON pigs developed NEC lesions by day 5 (0/11 vs. 11/13, P < 0.05). ANTI pigs had higher intestinal villi (+60%), digestive enzyme activities (+53–73%), and goblet cell densities (+110%) and lower myeloperoxidase (−51%) and colonic microbial density (105 vs. 1010 colony-forming units, all P < 0.05). Microarray transcriptomics showed strong downregulation of genes related to inflammation and innate immune response to microbiota and marked upregulation of genes related to amino acid metabolism, in particular threonine, glucose transport systems, and cell cycle in 5-day-old ANTI pigs. In a follow-up experiment, 5 days of antibiotics prevented NEC at least until day 10. Neonatal prophylactic antibiotics effectively reduced gut bacterial load, prevented NEC, intestinal atrophy, dysfunction, and inflammation and enhanced expression of genes related to gut metabolism and immunity in preterm pigs. PMID:24157972

Review of the systems biology of the immune system using agent-based models.

PubMed

Shinde, Snehal B; Kurhekar, Manish P

2018-06-01

The immune system is an inherent protection system in vertebrate animals including human beings that exhibit properties such as self-organisation, self-adaptation, learning, and recognition. It interacts with the other allied systems such as the gut and lymph nodes. There is a need for immune system modelling to know about its complex internal mechanism, to understand how it maintains the homoeostasis, and how it interacts with the other systems. There are two types of modelling techniques used for the simulation of features of the immune system: equation-based modelling (EBM) and agent-based modelling. Owing to certain shortcomings of the EBM, agent-based modelling techniques are being widely used. This technique provides various predictions for disease causes and treatments; it also helps in hypothesis verification. This study presents a review of agent-based modelling of the immune system and its interactions with the gut and lymph nodes. The authors also review the modelling of immune system interactions during tuberculosis and cancer. In addition, they also outline the future research directions for the immune system simulation through agent-based techniques such as the effects of stress on the immune system, evolution of the immune system, and identification of the parameters for a healthy immune system.

Vaccination with Recombinant Non-transmembrane Domain of Protein Mannosyltransferase 4 Improves Survival during Murine Disseminated Candidiasis.

PubMed

Wang, Li; Yan, Lan; Li, Xing Xing; Xu, Guo Tong; An, Mao Mao; Jiang, Yuan Ying

2015-01-01

Candida albicans is the most common cause of invasive fungal infections in humans. The C. albicans cell wall proteins play an important role in crucial host-fungus interactions and might be ideal vaccine targets to induce protective immune response in host. Meanwhile, protein that is specific to C. albicans is also an ideal target of vaccine. In this study, 11 proteins involving cell wall biosynthesis, yeast-to-hypha formation, or specific to C. albicans were chosen and were successfully cloned, purified and verified. The immune protection of vaccination with each recombinant protein respectively in preventing systemic candidiasis in BALB/c mice was assessed. The injection of rPmt4p vaccination significantly increased survival rate, decreased fungal burdens in the heart, liver, brain, and kidneys, and increased serum levels of both immunoglobulin G (IgG) and IgM against rPmt4p in the immunized mice. Histopathological assessment demonstrated that rPmt4p vaccination protected the tissue structure, and decreased the infiltration of inflammatory cells. Passive transfer of the rPmt4p immunized serum increased survival rate against murine systemic candidiasis and significantly reduced organ fungal burden. The immune serum enhanced mouse neutrophil killing activity by directly neutralizing rPmt4p effects in vitro. Levels of interleukin (IL)-4, IL-10, IL-12p70, IL-17A and tumor necrosis factor (TNF)-α in serum were higher in the immunized mice compared to those in the adjuvant control group. In conclusion, our results suggested that rPmt4p vaccination may be considered as a potential vaccine candidate against systemic candidiasis.

A parasitic helminth-derived peptide that targets the macrophage lysosome is a novel therapeutic option for autoimmune disease.

PubMed

Alvarado, Raquel; O'Brien, Bronwyn; Tanaka, Akane; Dalton, John P; Donnelly, Sheila

2015-02-01

Parasitic worms (helminths) reside in their mammalian hosts for many years. This is attributable, in part, to their ability to skew the host's immune system away from pro-inflammatory responses and towards anti-inflammatory or regulatory responses. This immune modulatory ability ensures helminth longevity within the host, while simultaneously minimises tissue destruction for the host. The molecules that the parasite releases clearly exert potent immune-modulatory actions, which could be exploited clinically, for example in the prophylactic and therapeutic treatment of pro-inflammatory and autoimmune diseases. We have identified a novel family of immune-modulatory proteins, termed helminth defence molecules (HDMs), which are secreted by several medically important helminth parasites. These HDMs share biochemical and structural characteristics with mammalian cathelicidin-like host defence peptides (HDPs), which are significant components of the innate immune system. Like their mammalian counterparts, parasite HDMs block the activation of macrophages via toll like receptor (TLR) 4 signalling, however HDMs are significantly less cytotoxic than HDPs. HDMs can traverse the cell membrane of macrophages and enter the endolysosomal system where they reduce the acidification of lysosomal compartments by inhibiting vacuolar (v)-ATPase activity. In doing this, HDMs can modulate critical cellular functions, such as cytokine secretion and antigen processing/presentation. Here, we review the role of macrophages, specifically their lysosomal mediated activities, in the initiation and perpetuation of pro-inflammatory immune responses. We also discuss the potential of helminth defence molecules (HDMs) as therapeutics to counteract the pro-inflammatory responses underlying autoimmune disease. Given the current lack of effective, non-cytotoxic treatment options to limit the progression of autoimmune pathologies, HDMs open novel treatment avenues. Crown Copyright © 2014. Published by Elsevier GmbH. All rights reserved.

Immune System Quiz

MedlinePlus

... Videos for Educators Search English Español Quiz: Immune System KidsHealth / For Kids / Quiz: Immune System Print How much do you know about your immune system? Find out by taking this quiz! About Us ...

Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sershen, Cheryl L.; Plimpton, Steven J.; May, Elebeoba E.

Mycobacterium tuberculosis associated granuloma formation can be viewed as a structural immune response that can contain and halt the spread of the pathogen. In several mammalian hosts, including non-human primates, Mtb granulomas are often hypoxic, although this has not been observed in wild type murine infection models. While a presumed consequence, the structural contribution of the granuloma to oxygen limitation and the concomitant impact on Mtb metabolic viability and persistence remains to be fully explored. We develop a multiscale computational model to test to what extent in vivo Mtb granulomas become hypoxic, and investigate the effects of hypoxia on hostmore » immune response efficacy and mycobacterial persistence. Our study integrates a physiological model of oxygen dynamics in the extracellular space of alveolar tissue, an agent-based model of cellular immune response, and a systems biology-based model of Mtb metabolic dynamics. Our theoretical studies suggest that the dynamics of granuloma organization mediates oxygen availability and illustrates the immunological contribution of this structural host response to infection outcome. Furthermore, our integrated model demonstrates the link between structural immune response and mechanistic drivers influencing Mtbs adaptation to its changing microenvironment and the qualitative infection outcome scenarios of clearance, containment, dissemination, and a newly observed theoretical outcome of transient containment. We observed hypoxic regions in the containment granuloma similar in size to granulomas found in mammalian in vivo models of Mtb infection. In the case of the containment outcome, our model uniquely demonstrates that immune response mediated hypoxic conditions help foster the shift down of bacteria through two stages of adaptation similar to thein vitro non-replicating persistence (NRP) observed in the Wayne model of Mtb dormancy. Lastly, the adaptation in part contributes to the ability of Mtb to remain dormant for years after initial infection.« less

Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach

DOE PAGES

Sershen, Cheryl L.; Plimpton, Steven J.; May, Elebeoba E.

2016-02-15

Mycobacterium tuberculosis associated granuloma formation can be viewed as a structural immune response that can contain and halt the spread of the pathogen. In several mammalian hosts, including non-human primates, Mtb granulomas are often hypoxic, although this has not been observed in wild type murine infection models. While a presumed consequence, the structural contribution of the granuloma to oxygen limitation and the concomitant impact on Mtb metabolic viability and persistence remains to be fully explored. We develop a multiscale computational model to test to what extent in vivo Mtb granulomas become hypoxic, and investigate the effects of hypoxia on hostmore » immune response efficacy and mycobacterial persistence. Our study integrates a physiological model of oxygen dynamics in the extracellular space of alveolar tissue, an agent-based model of cellular immune response, and a systems biology-based model of Mtb metabolic dynamics. Our theoretical studies suggest that the dynamics of granuloma organization mediates oxygen availability and illustrates the immunological contribution of this structural host response to infection outcome. Furthermore, our integrated model demonstrates the link between structural immune response and mechanistic drivers influencing Mtbs adaptation to its changing microenvironment and the qualitative infection outcome scenarios of clearance, containment, dissemination, and a newly observed theoretical outcome of transient containment. We observed hypoxic regions in the containment granuloma similar in size to granulomas found in mammalian in vivo models of Mtb infection. In the case of the containment outcome, our model uniquely demonstrates that immune response mediated hypoxic conditions help foster the shift down of bacteria through two stages of adaptation similar to thein vitro non-replicating persistence (NRP) observed in the Wayne model of Mtb dormancy. Lastly, the adaptation in part contributes to the ability of Mtb to remain dormant for years after initial infection.« less

Foot-and-mouth disease virus non-structural protein 3A inhibits the interferon-β signaling pathway

PubMed Central

Li, Dan; Lei, Caoqi; Xu, Zhisheng; Yang, Fan; Liu, Huanan; Zhu, Zixiang; Li, Shu; Liu, Xiangtao; Shu, Hongbing; Zheng, Haixue

2016-01-01

Foot-and-mouth disease virus (FMDV) is the etiological agent of FMD, which affects cloven-hoofed animals. The pathophysiology of FMDV has not been fully understood and the evasion of host innate immune system is still unclear. Here, the FMDV non-structural protein 3A was identified as a negative regulator of virus-triggered IFN-β signaling pathway. Overexpression of the FMDV 3A inhibited Sendai virus-triggered activation of IRF3 and the expressions of RIG-I/MDA5. Transient transfection and co-immunoprecipitation experiments suggested that FMDV 3A interacts with RIG-I, MDA5 and VISA, which is dependent on the N-terminal 51 amino acids of 3A. Furthermore, 3A also inhibited the expressions of RIG-I, MDA5, and VISA by disrupting their mRNA levels. These results demonstrated that 3A inhibits the RLR-mediated IFN-β induction and uncovered a novel mechanism by which the FMDV 3A protein evades the host innate immune system. PMID:26883855

The meninges: new therapeutic targets for multiple sclerosis.

PubMed

Russi, Abigail E; Brown, Melissa A

2015-02-01

The central nervous system (CNS) largely comprises nonregenerating cells, including neurons and myelin-producing oligodendrocytes, which are particularly vulnerable to immune cell-mediated damage. To protect the CNS, mechanisms exist that normally restrict the transit of peripheral immune cells into the brain and spinal cord, conferring an "immune-specialized" status. Thus, there has been a long-standing debate as to how these restrictions are overcome in several inflammatory diseases of the CNS, including multiple sclerosis (MS). In this review, we highlight the role of the meninges, tissues that surround and protect the CNS and enclose the cerebral spinal fluid, in promoting chronic inflammation that leads to neuronal damage. Although the meninges have traditionally been considered structures that provide physical protection for the brain and spinal cord, new data have established these tissues as sites of active immunity. It has been hypothesized that the meninges are important players in normal immunosurveillance of the CNS but also serve as initial sites of anti-myelin immune responses. The resulting robust meningeal inflammation elicits loss of localized blood-brain barrier (BBB) integrity and facilitates a large-scale influx of immune cells into the CNS parenchyma. We propose that targeting the cells and molecules mediating these inflammatory responses within the meninges offers promising therapies for MS that are free from the constraints imposed by the BBB. Importantly, such therapies may avoid the systemic immunosuppression often associated with the existing treatments. Copyright © 2015 Elsevier Inc. All rights reserved.

Resilience of biochemical activity in protein domains in the face of structural divergence.

PubMed

Zhang, Dapeng; Iyer, Lakshminarayan M; Burroughs, A Maxwell; Aravind, L

2014-06-01

Recent studies point to the prevalence of the evolutionary phenomenon of drastic structural transformation of protein domains while continuing to preserve their basic biochemical function. These transformations span a wide spectrum, including simple domains incorporated into larger structural scaffolds, changes in the structural core, major active site shifts, topological rewiring and extensive structural transmogrifications. Proteins from biological conflict systems, such as toxin-antitoxin, restriction-modification, CRISPR/Cas, polymorphic toxin and secondary metabolism systems commonly display such transformations. These include endoDNases, metal-independent RNases, deaminases, ADP ribosyltransferases, immunity proteins, kinases and E1-like enzymes. In eukaryotes such transformations are seen in domains involved in chromatin-related peptide recognition and protein/DNA-modification. Intense selective pressures from 'arms-race'-like situations in conflict and macromolecular modification systems could favor drastic structural divergence while preserving function. Published by Elsevier Ltd.

Immune System Dysfunction in the Elderly.

PubMed

Fuentes, Eduardo; Fuentes, Manuel; Alarcón, Marcelo; Palomo, Iván

2017-01-01

Human aging is characterized by both physical and physiological frailty that profoundly affects the immune system. In this context aging is associated with declines in adaptive and innate immunity established as immunosenescence. Immunosenescence is a new concept that reflects the age-associated restructuring changes of innate and adaptive immune functions. Thus elderly individuals usually present chronic low-level inflammation, higher infection rates and chronic diseases. A study of alterations in the immune system during aging could provide a potentially useful biomarker for the evaluation of immune senescence treatment. The immune system is the result of the interplay between innate and adaptive immunity, yet the impact of aging on this function is unclear. In this article the function of the immune system during aging is explored.

Innate immune memory in plants.

PubMed

Reimer-Michalski, Eva-Maria; Conrath, Uwe

2016-08-01

The plant innate immune system comprises local and systemic immune responses. Systemic plant immunity develops after foliar infection by microbial pathogens, upon root colonization by certain microbes, or in response to physical injury. The systemic plant immune response to localized foliar infection is associated with elevated levels of pattern-recognition receptors, accumulation of dormant signaling enzymes, and alterations in chromatin state. Together, these systemic responses provide a memory to the initial infection by priming the remote leaves for enhanced defense and immunity to reinfection. The plant innate immune system thus builds immunological memory by utilizing mechanisms and components that are similar to those employed in the trained innate immune response of jawed vertebrates. Therefore, there seems to be conservation, or convergence, in the evolution of innate immune memory in plants and vertebrates. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Immune system and tumors].

PubMed

Terme, Magali; Tanchot, Corinne

2017-02-01

Despite having been much debated, it is now well established that the immune system plays an essential role in the fight against cancer. In this article, we will highlight the implication of the immune system in the control of tumor growth and describe the major components of the immune system involved in the antitumoral immune response. The immune system, while exerting pressure on tumor cells, also will play a pro-tumoral role by sculpting the immunogenicity of tumors cells as they develop. Finally, we will illustrate the numerous mechanisms of immune suppression that take place within the tumoral microenvironment which allow tumor cells to escape control from the immune system. The increasingly precise knowledge of the brakes to an effective antitumor immune response allows the development of immunotherapy strategies more and more innovating and promising of hope. Copyright © 2016. Published by Elsevier Masson SAS.

Structural diversity of Burkholderia pseudomallei lipopolysaccharides affects innate immune signaling

PubMed Central

Norris, Michael H.; Schweizer, Herbert P.

2017-01-01

Burkholderia pseudomallei (Bp) causes the disease melioidosis. The main cause of mortality in this disease is septic shock triggered by the host responding to lipopolysaccharide (LPS) components of the Gram-negative outer membrane. Bp LPS is thought to be a weak inducer of the host immune system. LPS from several strains of Bp were purified and their ability to induce the inflammatory mediators TNF-α and iNOS in murine macrophages at low concentrations was investigated. Innate and adaptive immunity qPCR arrays were used to profile expression patterns of 84 gene targets in response to the different LPS types. Additional qPCR validation confirmed large differences in macrophage response. LPS from a high-virulence serotype B strain 576a and a virulent rough central nervous system tropic strain MSHR435 greatly induced the innate immune response indicating that the immunopathogenesis of these strains is different than in infections with strains similar to the prototype strain 1026b. The accumulation of autophagic vesicles was also increased in macrophages challenged with highly immunogenic Bp LPS. Gene induction and concomitant cytokine secretion profiles of human PBMCs in response to the various LPS were also investigated. MALDI-TOF/TOF was used to probe the lipid A portions of the LPS, indicating substantial structural differences that likely play a role in host response to LPS. These findings add to the evolving knowledge of host-response to bacterial LPS, which can be used to better understand septic shock in melioidosis patients and in the rational design of vaccines. PMID:28453531

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.

A study of the Immune Epitope Database for some fungi species using network topological indices.

PubMed

Vázquez-Prieto, Severo; Paniagua, Esperanza; Solana, Hugo; Ubeira, Florencio M; González-Díaz, Humberto

2017-08-01

In the last years, the encryption of system structure information with different network topological indices has been a very active field of research. In the present study, we assembled for the first time a complex network using data obtained from the Immune Epitope Database for fungi species, and we then considered the general topology, the node degree distribution, and the local structure of this network. We also calculated eight node centrality measures for the observed network and compared it with three theoretical models. In view of the results obtained, we may expect that the present approach can become a valuable tool to explore the complexity of this database, as well as for the storage, manipulation, comparison, and retrieval of information contained therein.

[Clinical and immunological study of the relationship of the digestive system chronic diseases and atherosclerosis in the basin of the abdominal aorta in elderly patients].

PubMed

Dolgushina, A I; Shaposhnik, I I; Volchegorskiĭ, I A

2014-01-01

Paper describes clinical and immunological study about the relationship between chronic diseases of the digestive system and atherosclerosis in the basin of the abdominal aorta in patients of elderly and senile age. There were revealed the structural and clinical features of the gastrointestinal tract diseases, depending on the extent of atherosclerosis in the basin of the abdominal aorta. Evaluation of the immune status included the determination of lymphocyte subpopulation composition, the functional state of neutrophils and cytokine levels. It is found that the progression of atherosclerosis in the basin of the abdominal aorta in patients of elderly and senile age with chronic diseases of the digestive system was accompanied by the activation of pro-inflammatory mechanisms of the immune system and the accompanying intensification of oxidative stress.

Autoantibodies against complement components in systemic lupus erythematosus - role in the pathogenesis and clinical manifestations.

PubMed

Hristova, M H; Stoyanova, V S

2017-12-01

Many complement structures and a number of additional factors, i.e. autoantibodies, receptors, hormones and cytokines, are implicated in the complex pathogenesis of systemic lupus erythematosus. Genetic defects in the complement as well as functional deficiency due to antibodies against its components lead to different pathological conditions, usually clinically presented. Among them hypocomplementemic urticarial vasculitis, different types of glomerulonephritis as dense deposit disease, IgA nephropathy, atypical haemolytic uremic syndrome and lupus nephritis are very common. These antibodies cause conformational changes leading to pathological activation or inhibition of complement with organ damage and/or limited capacity of the immune system to clear immune complexes and apoptotic debris. Finally, we summarize the role of complement antibodies in the pathogenesis of systemic lupus erythematosus and discuss the mechanism of some related clinical conditions such as infections, thyroiditis, thrombosis, acquired von Willebrand disease, etc.

Identification and expressional analysis of NLRC5 inflammasome gene in smolting Atlantic salmon (Salmo salar).

PubMed

Pontigo, Juan Pablo; Agüero, María José; Sánchez, Patricio; Oyarzún, Ricardo; Vargas-Lagos, Carolina; Mancilla, Jorge; Kossmann, Hans; Morera, Francisco J; Yáñez, Alejandro J; Vargas-Chacoff, Luis

2016-11-01

The NOD-like receptors (NLRs) were recently identified as an intracellular pathogen recognition receptor family in vertebrates. While the immune system participation of NLRs has been characterized and analyzed in various mammalian models, few studies have considered NLRs in teleost species. Therefore, this study analyzed the Atlantic salmon (Salmo salar) NLRC5. Structurally, Atlantic salmon NLRC5 presented leucine-rich repeat subfamily genes. Phylogenetically, NLRC5 was moderately conserved between S. salar and other species. Real-time quantitative PCR revealed NLRC5 expression in almost all analyzed organs, with greatest expressions in the head kidney, spleen, and hindgut. Furthermore, NLRC5 gene expression decreased during smolt stage. These data suggest that NLRC5 participates in the Atlantic salmon immune response and is regulated, at least partly, by the smoltification process, suggesting that there is a depression of immune system from parr at smolt stage. This is the first report on the NLRC5 gene in salmonid smolts. Copyright © 2016 Elsevier Ltd. All rights reserved.

Steroidogenesis in the skin: implications for local immune functions

PubMed Central

Slominski, Andrzej; Zbytek, Bazej; Nikolakis, Georgios; Manna, Pulak R.; Skobowiat, Cezary; Zmijewski, Michal; Li, Wei; Janjetovic, Zorica; Postlethwaite, Arnold; Zouboulis, Christos C.; Tuckey, Robert C.

2013-01-01

The skin has developed a hierarchy of systems that encompasses the skin immune and local steroidogenic activities in order to protect the body against the external environment and biological factors and to maintain local homeostasis. Most recently it has been established that skin cells contain the entire biochemical apparatus necessary for production of glucocorticoids, androgens and estrogens either from precursors of systemic origin or, alternatively, through the conversion of cholesterol to pregnenolone and its subsequent transformation to biologically active steroids. Examples of these products are corticosterone, cortisol, testosterone, dihydrotesterone and estradiol. Their local production can be regulated by locally produced corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) or cytokines. Furthermore the production of glucocorticoids is affected by ultraviolet B radiation. The level of production and nature of the final steroid products are dependent on the cell type or cutaneous compartment, e.g., epidermis, dermis, adnexal structures or adipose tissue. Locally produced glucocorticoids, androgens and estrogens affect functions of the epidermis and adnexal structures as well as local immune activity. Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases. The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens. Furthermore, local activity of CYP11A1 can produce novel 7 -steroids and secosteroids that are biologically active. Therefore, modulation of local steroidogenic activity may serve as a new therapeutic approach for treatment of inflammatory disorders, autoimmune processes or other skin disorders. In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases. PMID:23435015

Hazard identification and risk assessment for biologics targeting the immune system.

PubMed

Weir, Andrea B

2008-01-01

Biologic pharmaceuticals include a variety of products, such as monoclonal antibodies, fusion proteins and cytokines. Products in those classes include immunomodulatory biologics, which are intended to enhance or diminish the activity of the immune system. Immunomodulatory biologics have been approved by the U.S. FDA for a variety of indications, including cancer and inflammatory conditions. Prior to gaining approval for marketing, sponsoring companies for all types of products must demonstrate a product's safety in toxicology studies conducted in animals and show safety and efficacy in clinical trials conducted in patients. The overall goal of toxicology studies, which applies to immunomodulatory and other product types, is to identify the hazards that products pose to humans. Because biologics are generally highly selective for specific targets (receptors/epitopes), conducting toxicology studies in animal models with the target is essential. Such animals are referred to as pharmacologically relevant. Endpoints routinely included in toxicology studies, such as hematology, organ weight and histopathology, can be used to assess the effect of a product on the structure of the immune system. Additionally, specialized endpoints, such as immunophenotyping and immune function tests, can be used to define effects of immunomodulatory products on the immune system. Following hazard identification, risks posed to patients are assessed and managed. Risks can be managed through clinical trial design and risk communication, a practice that applies to immunomodulatory and other product types. Examples of risk management in clinical trial design include establishing a safe starting dose, defining the appropriate patient population and establishing appropriate patient monitoring. Risk communication starts during clinical trials and continues after product approval. A combination of hazard identification, risk assessment and risk management allows for drug development to proceed with minimum risks to patients.

Probiotics, antibiotics and the immune responses to vaccines

PubMed Central

Praharaj, Ira; John, Sushil M.; Bandyopadhyay, Rini; Kang, Gagandeep

2015-01-01

Orally delivered vaccines have been shown to perform poorly in developing countries. There are marked differences in the structure and the luminal environment of the gut in developing countries resulting in changes in immune and barrier function. Recent studies using newly developed technology and analytic methods have made it increasingly clear that the intestinal microbiota activate a multitude of pathways that control innate and adaptive immunity in the gut. Several hypotheses have been proposed for the underperformance of oral vaccines in developing countries, and modulation of the intestinal microbiota is now being tested in human clinical trials. Supplementation with specific strains of probiotics has been shown to have modulatory effects on intestinal and systemic immune responses in animal models and forms the basis for human studies with vaccines. However, most studies published so far that have evaluated the immune response to vaccines in children and adults have been small and results have varied by age, antigen, type of antibody response and probiotic strain. Use of anthelminthic drugs in children has been shown to possibly increase immunogenicity following oral cholera vaccination, lending further support to the rationale for modulation of the immune response to oral vaccination through the intestinal microbiome. PMID:25964456

Operational Efficiency of an Immunization Clinic Attached to Rural Health Training Centre in Delhi, India: A Time and Motion Study

PubMed Central

Kumar, Varun; Mangal, Abha; Panesar, Sanjeet; Yadav, Geeta; Talwar, Richa; Raut, Deepak; Singh, Saudan

2014-01-01

Background. Obtaining baseline data about current patterns of work is important for assessing the effects of interventions designed to improve care delivery. Time and motion studies allow for the most accurate measurement of structured components. Therefore, the present study was conducted to study the operational efficiency of an immunization clinic in Delhi, India. Methods. An observational cross-sectional study was conducted at the immunization clinic of Rural Health Training Centre in Delhi, India, from January 2014 to March 2014. The study composed two stage evaluations, a passive observation and a time and motion study. Systemic random sampling method was used to select 863 mothers/caregivers attending the immunization clinic. Results. At the immunization clinic, the study participants spent 64.1% of their total time in waiting. For new cases, the mean time taken for initial registration and receiving postvaccination advice was found to be significantly longer than old cases. Delivering health care services took more time during Mondays and also during the first hour of the day. Conclusion. Results of this study will guide public health decision-makers at all government levels in planning and implementation of immunization programs in developing countries. PMID:25431679

The Immune Interplay between the Host and the Pathogen in Aspergillus fumigatus Lung Infection

PubMed Central

Sales-Campos, Helioswilton; Tonani, Ludmilla; Cardoso, Cristina Ribeiro Barros; Kress, Márcia Regina Von Zeska

2013-01-01

The interplay between Aspergillus fumigatus and the host immune response in lung infection has been subject of studies over the last years due to its importance in immunocompromised patients. The multifactorial virulence factors of A. fumigatus are related to the fungus biological characteristics, for example, structure, ability to grow and adapt to high temperatures and stress conditions, besides capability of evading the immune system and causing damage to the host. In this context, the fungus recognition by the host innate immunity occurs when the pathogen disrupts the natural and chemical barriers followed by the activation of acquired immunity. It seems clear that a Th1 response has a protective role, whereas Th2 reactions are often associated with higher fungal burden, and Th17 response is still controversial. Furthermore, a fine regulation of the effector immunity is required to avoid excessive tissue damage associated with fungal clearance, and this role could be attributed to regulatory T cells. Finally, in this work we reviewed the aspects involved in the complex interplay between the host immune response and the pathogen virulence factors, highlighting the immunological issues and the importance of its better understanding to the development of novel therapeutic approaches for invasive lung aspergillosis. PMID:23984400

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 simulator. The abnormal conditions considered in this work include locked actuators (stabilator, aileron, rudder, and throttle), structural damage of the wing, horizontal tail, and vertical tail, malfunctioning sensors, and reduced engine effectiveness. The results of applying the proposed approach to this wide range of abnormal conditions show its high capability in detecting the abnormal conditions with zero false alarms and very high detection rates, correctly identifying the failed subsystem and evaluating the type and severity of the failure. The results also reveal that the post-failure flight envelope can be reasonably predicted within this framework.

Exploring the Homeostatic and Sensory Roles of the Immune System.

PubMed

Marques, Rafael Elias; Marques, Pedro Elias; Guabiraba, Rodrigo; Teixeira, Mauro Martins

2016-01-01

Immunology developed under the notion of the immune system exists to fight pathogens. Recently, the discovery of interactions with commensal microbiota that are essential to human health initiated a change in this old paradigm. Here, we argue that the immune system has major physiological roles extending far beyond defending the host. Immune and inflammatory responses share the core property of sensing, defining the immune system also as a sensory system. The inference with the immune system collects, interprets, and stores information, while creating an identity of self, places it in close relationship to the nervous system, which suggests that these systems may have a profound evolutionary connection.

Immunization Information System and Informatics to Promote Immunizations: Perspective From Minnesota Immunization Information Connection.

PubMed

Muscoplat, Miriam Halstead; Rajamani, Sripriya

2017-01-01

The vision for management of immunization information is availability of real-time consolidated data and services for all ages, to clinical, public health, and other stakeholders. This is being executed through Immunization Information Systems (IISs), which are population-based and confidential computerized systems present in most US states and territories. Immunization Information Systems offer many functionalities, such as immunization assessment reports, client follow-up, reminder/recall feature, vaccine management tools, state-supplied vaccine ordering, comprehensive immunization history, clinical decision support/vaccine forecasting and recommendations, data processing, and data exchange. This perspective article will present various informatics tools in an IIS, in the context of the Minnesota Immunization Information Connection.

Structure, Biology, and Therapeutic Application of Toxin-Antitoxin Systems in Pathogenic Bacteria.

PubMed

Lee, Ki-Young; Lee, Bong-Jin

2016-10-22

Bacterial toxin-antitoxin (TA) systems have received increasing attention for their diverse identities, structures, and functional implications in cell cycle arrest and survival against environmental stresses such as nutrient deficiency, antibiotic treatments, and immune system attacks. In this review, we describe the biological functions and the auto-regulatory mechanisms of six different types of TA systems, among which the type II TA system has been most extensively studied. The functions of type II toxins include mRNA/tRNA cleavage, gyrase/ribosome poison, and protein phosphorylation, which can be neutralized by their cognate antitoxins. We mainly explore the similar but divergent structures of type II TA proteins from 12 important pathogenic bacteria, including various aspects of protein-protein interactions. Accumulating knowledge about the structure-function correlation of TA systems from pathogenic bacteria has facilitated a novel strategy to develop antibiotic drugs that target specific pathogens. These molecules could increase the intrinsic activity of the toxin by artificially interfering with the intermolecular network of the TA systems.

As-CATH1-6, novel cathelicidins with potent antimicrobial and immunomodulatory properties from Alligator sinensis, play pivotal roles in host antimicrobial immune responses.

PubMed

Chen, Yan; Cai, Shasha; Qiao, Xue; Wu, Mali; Guo, Zhilai; Wang, Renping; Kuang, Yi-Qun; Yu, Haining; Wang, Yipeng

2017-08-10

Crocodilians are regarded as possessing a powerful immune system. However, the composition and action of the crocodilian immune system have remained unclear until now. Cathelicidins, the principal family of host defense peptides, play pivotal roles in vertebrate immune defense against microbial invasions. However, cathelicidins from crocodilians have not been extensively studied to date. In the present study, six novel cathelicidins (As-CATH1-6) were identified and characterized from the endangered Chinese alligator ( Alligator sinensis ). As-CATH1-6 exhibit no sequence similarity with any of the known cathelicidins. Structure analysis indicated that As-CATH1-3 adopt a random coil secondary conformation, whereas As-CATH4-6 were predicted to mainly adopt an amphipathic α-helix conformation. Among them, As-CATH4-6 exhibited potent, broad-spectrum and rapid antimicrobial activity by inducing the disruption of cell membrane integrity. They also exhibited strong ability to prevent the formation of bacterial biofilms and eradicate preformed biofilms. Furthermore, As-CATH4-6 exhibited potent anti-inflammatory activity by inhibiting the lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and pro-inflammatory cytokines in mouse peritoneal macrophages. They directly neutralized LPS toxicity and therefore inhibited the binding of LPS to the TLR4 receptor and the subsequent activation of inflammatory response pathways. In a peritonitis mice model, As-CATH2-6 provided effective protection against bacterial infection through enhanced immune cell recruitment. In the host Chinese alligator, As-CATH1-6 are mainly expressed in immune organs and epithelial tissues. Bacterial infection significantly enhances their expression, which implies an important role in host anti-infective response. Taken together, the diversity and multiple functions of As-CATH1-6 partially reveal the powerful immune system of the Chinese alligator. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Autoimmune therapies targeting costimulation and emerging trends in multivalent therapeutics.

PubMed

Chittasupho, Chuda; Siahaan, Teruna J; Vines, Charlotte M; Berkland, Cory

2011-07-01

Proteins participating in immunological signaling have emerged as important targets for controlling the immune response. A multitude of receptor-ligand pairs that regulate signaling pathways of the immune response have been identified. In the complex milieu of immune signaling, therapeutic agents targeting mediators of cellular signaling often either activate an inflammatory immune response or induce tolerance. This review is primarily focused on therapeutics that inhibit the inflammatory immune response by targeting membrane-bound proteins regulating costimulation or mediating immune-cell adhesion. Many of these signals participate in larger, organized structures such as the immunological synapse. Receptor clustering and arrangement into organized structures is also reviewed and emerging trends implicating a potential role for multivalent therapeutics is posited.

In immune defense: redefining the role of the immune system in chronic disease.

PubMed

Rubinow, Katya B; Rubinow, David R

2017-03-01

The recognition of altered immune system function in many chronic disease states has proven to be a pivotal advance in biomedical research over the past decade. For many metabolic and mood disorders, this altered immune activity has been characterized as inflammation, with the attendant assumption that the immune response is aberrant. However, accumulating evidence challenges this assumption and suggests that the immune system may be mounting adaptive responses to chronic stressors. Further, the inordinate complexity of immune function renders a simplistic, binary model incapable of capturing critical mechanistic insights. In this perspective article, we propose alternative paradigms for understanding the role of the immune system in chronic disease. By invoking allostasis or systems biology rather than inflammation, we can ascribe greater functional significance to immune mediators, gain newfound appreciation of the adaptive facets of altered immune activity, and better avoid the potentially disastrous effects of translating erroneous assumptions into novel therapeutic strategies.

Roles of microRNA in the immature immune system of neonates.

PubMed

Yu, Hong-Ren; Huang, Lien-Hung; Li, Sung-Chou

2018-06-13

Neonates have an immature immune system; therefore, their immune activities are different from the activities of adult immune systems. Such differences between neonates and adults are reflected by cell population constitutions, immune responses, cytokine production, and the expression of cellular/humoral molecules, which contribute to the specific neonatal microbial susceptibility and atopic properties. MicroRNAs (miRNAs) have been discovered to modulate many aspects of immune responses. Herein, we summarize the distinct manifestations of the neonatal immune system, including cellular and non-cellular components. We also review the current findings on the modulatory effects of miRNAs on the neonatal immune system. These findings suggest that miRNAs have the potential to be useful therapeutic targets for certain infection or inflammatory conditions by modulating the neonatal immune system. In the future, we need a more comprehensive understanding in regard to miRNAs and how they modulate specific immune cells in neonates. Copyright © 2018. Published by Elsevier B.V.

Strengthening health system to improve immunization for migrants in China.

PubMed

Fang, Hai; Yang, Li; Zhang, Huyang; Li, Chenyang; Wen, Liankui; Sun, Li; Hanson, Kara; Meng, Qingyue

2017-07-01

Immunization is the most cost-effective method to prevent and control vaccine-preventable diseases. Migrant population in China has been rising rapidly, and their immunization status is poor. China has tried various strategies to strengthen its health system, which has significantly improved immunization for migrants. This study applied a qualitative retrospective review method aiming to collect, analyze and synthesize health system strengthening experiences and practices about improving immunizations for migrants in China. A conceptual framework of Theory of Change was used to extract the searched literatures. 11 searched literatures and 4 national laws and policies related to immunizations for migrant children were carefully studied. China mainly employed 3 health system strengthening strategies to significantly improve immunization for migrant population: stop charging immunization fees or immunization insurance, manage immunization certificates well, and pay extra attentions on immunization for special children including migrant children. These health system strengthening strategies were very effective, and searched literatures show that up-to-date and age-appropriate immunization rates were significantly improved for migrant children. Economic development led to higher migrant population in China, but immunization for migrants, particularly migrant children, were poor. Fortunately various health system strengthening strategies were employed to improve immunization for migrants in China and they were rather successful. The experiences and lessons of immunization for migrant population in China might be helpful for other developing countries with a large number of migrant population.

Glycomaterials for probing host–pathogen interactions and the immune response

PubMed Central

Huang, Mia L; Fisher, Christopher J

2016-01-01

The initial engagement of host cells by pathogens is often mediated by glycan structures presented on the cell surface. Various components of the glycocalyx can be targeted by pathogens for adhesion to facilitate infection. Glycans also play integral roles in the modulation of the host immune response to infection. Therefore, understanding the parameters that define glycan interactions with both pathogens and the various components of the host immune system can aid in the development of strategies to prevent, interrupt, or manage infection. Glycomaterials provide a unique and powerful tool with which to interrogate the compositional and functional complexity of the glycocalyx. The objective of this review is to highlight some key contributions from this area of research in deciphering the mechanisms of pathogenesis and the associated host response. PMID:27190259

Bacterial effectors target the common signaling partner BAK1 to disrupt multiple MAMP receptor-signaling complexes and impede plant immunity.

PubMed

Shan, Libo; He, Ping; Li, Jianming; Heese, Antje; Peck, Scott C; Nürnberger, Thorsten; Martin, Gregory B; Sheen, Jen

2008-07-17

Successful pathogens have evolved strategies to interfere with host immune systems. For example, the ubiquitous plant pathogen Pseudomonas syringae injects two sequence-distinct effectors, AvrPto and AvrPtoB, to intercept convergent innate immune responses stimulated by multiple microbe-associated molecular patterns (MAMPs). However, the direct host targets and precise molecular mechanisms of bacterial effectors remain largely obscure. We show that AvrPto and AvrPtoB bind the Arabidopsis receptor-like kinase BAK1, a shared signaling partner of both the flagellin receptor FLS2 and the brassinosteroid receptor BRI1. This targeting interferes with ligand-dependent association of FLS2 with BAK1 during infection. It also impedes BAK1-dependent host immune responses to diverse other MAMPs and brassinosteroid signaling. Significantly, the structural basis of AvrPto-BAK1 interaction appears to be distinct from AvrPto-Pto association required for effector-triggered immunity. These findings uncover a unique strategy of bacterial pathogenesis where virulence effectors block signal transmission through a key common component of multiple MAMP-receptor complexes.

Modeled Microgravity Inhibits Apoptosis in Peripheral Blood Lymphocytes

NASA Technical Reports Server (NTRS)

Risin, Diana; Pellis, Neal R.

1999-01-01

Impairment of the immunity in astronauts and cosmonauts even in short term flights is a recognized risk. Long term orbital space missions and anticipated interplanetary flights increase the concern for more pronounced effects on the immune system with potential clinical consequences. Impairment of the immunity in space may be due tonumerous physiological changes caused by space-related factors, which in turn affect the immune system, or alternatively, it may be due to direct effects of different factors encountered in space on lymphoid cells and their interactions. Indeed, in modeled microgravity (MMG) experiments on Earth we and others showed that microgravity directly affects multiple lymphocyte functions. It interferes with expression of cell surface molecules, causes inhibition of lymphocyte locomotion, suppresses polyclopal and antigen-specific lymphocyte activation, selectively inhibits protein kinase C (PKC) isoforms. Some of these effects were also confirmed in cell culture experiments in real space conditions during Spacelab, Biokosmos and Shuttle Missions. The results of these studies, taken together, strongly indicated that microgravity interferes with fundamental biological processes associated with functional and structural changes in cell surface membranes, cell surface molecules and in their interaction. Based on the data and on their interpretation, we hypothesized that microgravity in addition to observed functional changes affects programmed cell death (PCD) in lymphocyte populations and that this mechanism could contribute to the impairment of the immunity.

Initiation of the TLR4 signal transduction network : deeper understanding for better therapeutics.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Branda, Steven S.; Hayden, Carl C.; Sherman, Michael Y.

2010-09-01

The innate immune system represents our first line of defense against microbial pathogens, and in many cases is activated by recognition of pathogen cellular components (dsRNA, flagella, LPS, etc.) by cell surface membrane proteins known as toll-like receptors (TLRs). As the initial trigger for innate immune response activation, TLRs also represent a means by which we can effectively control or modulate inflammatory responses. This proposal focused on TLR4, which is the cell-surface receptor primarily responsible for initiating the innate immune response to lipopolysaccharide (LPS), a major component of the outer membrane envelope of gram-negative bacteria. The goal was to bettermore » understand TLR4 activation and associated membrane proximal events, in order to enhance the design of small molecule therapeutics to modulate immune activation. Our approach was to reconstitute the receptor in biomimetic systems in-vitro to allow study of the structure and dynamics with biophysical methods. Structural studies were initiated in the first year but were halted after the crystal structure of the dimerized receptor was published early in the second year of the program. Methods were developed to determine the association constant for oligomerization of the soluble receptor. LPS-induced oligomerization was observed to be a strong function of buffer conditions. In 20 mM Tris pH 8.0 with 200 mM NaCl, the onset of receptor oligomerization occurred at 0.2 uM TLR4/MD2 with E coli LPS Ra mutant in excess. However, in the presence of 0.5 uM CD14 and 0.5 uM LBP, the onset of receptor oligomerization was observed to be less than 10 nM TLR4/MD2. Several methods were pursued to study LPS-induced oligomerization of the membrane-bound receptor, including CryoEM, FRET, colocalization and codiffusion followed by TIRF, and fluorescence correlation spectroscopy. However, there approaches met with only limited success.« less

Immune System Toxicity and Immunotoxicity Hazard Identification

EPA Science Inventory

Exposure to chemicals may alter immune system health, increasing the risk of infections, allergy and autoimmune diseases. The chapter provides a concise overview of the immune system, host factors that affect immune system heal, and the effects that xenobiotic exposure may have ...

Conceptual Spaces of the Immune System.

PubMed

Fierz, Walter

2016-01-01

The immune system can be looked at as a cognitive system. This is often done in analogy to the neuro-psychological system. Here, it is demonstrated that the cognitive functions of the immune system can be properly described within a new theory of cognitive science. Gärdenfors' geometrical framework of conceptual spaces is applied to immune cognition. Basic notions, like quality dimensions, natural properties and concepts, similarities, prototypes, saliences, etc., are related to cognitive phenomena of the immune system. Constraints derived from treating the immune system within a cognitive theory, like Gärdenfors' conceptual spaces, might well prove to be instrumental for the design of vaccines, immunological diagnostic tests, and immunotherapy.

The two sides of complement C3d: evolution of electrostatics in a link between innate and adaptive immunity.

PubMed

Kieslich, Chris A; Morikis, Dimitrios

2012-01-01

The interaction between complement fragment C3d and complement receptor 2 (CR2) is a key aspect of complement immune system activation, and is a component in a link between innate and adaptive immunities. The complement immune system is an ancient mechanism for defense, and can be found in species that have been on Earth for the last 600 million years. However, the link between the complement system and adaptive immunity, which is formed through the association of the B-cell co-receptor complex, including the C3d-CR2 interaction, is a much more recent adaptation. Human C3d and CR2 have net charges of -1 and +7 respectively, and are believed to have evolved favoring the role of electrostatics in their functions. To investigate the role of electrostatics in the function and evolution of human C3d and CR2, we have applied electrostatic similarity methods to identify regions of evolutionarily conserved electrostatic potential based on 24 homologues of complement C3d and 4 homologues of CR2. We also examine the effects of structural perturbation, as introduced through molecular dynamics and mutations, on spatial distributions of electrostatic potential to identify perturbation resistant regions, generated by so-called electrostatic "hot-spots". Distributions of electrostatic similarity based on families of perturbed structures illustrate the presence of electrostatic "hot-spots" at the two functional sites of C3d, while the surface of CR2 lacks electrostatic "hot-spots" despite its excessively positive nature. We propose that the electrostatic "hot-spots" of C3d have evolved to optimize its dual-functionality (covalently attaching to pathogen surfaces and interaction with CR2), which are both necessary for the formation B-cell co-receptor complexes. Comparison of the perturbation resistance of the electrostatic character of the homologues of C3d suggests that there was an emergence of a new role of electrostatics, and a transition in the function of C3d, after the divergence of jawless fish.

The Two Sides of Complement C3d: Evolution of Electrostatics in a Link between Innate and Adaptive Immunity

PubMed Central

Kieslich, Chris A.; Morikis, Dimitrios

2012-01-01

The interaction between complement fragment C3d and complement receptor 2 (CR2) is a key aspect of complement immune system activation, and is a component in a link between innate and adaptive immunities. The complement immune system is an ancient mechanism for defense, and can be found in species that have been on Earth for the last 600 million years. However, the link between the complement system and adaptive immunity, which is formed through the association of the B-cell co-receptor complex, including the C3d-CR2 interaction, is a much more recent adaptation. Human C3d and CR2 have net charges of −1 and +7 respectively, and are believed to have evolved favoring the role of electrostatics in their functions. To investigate the role of electrostatics in the function and evolution of human C3d and CR2, we have applied electrostatic similarity methods to identify regions of evolutionarily conserved electrostatic potential based on 24 homologues of complement C3d and 4 homologues of CR2. We also examine the effects of structural perturbation, as introduced through molecular dynamics and mutations, on spatial distributions of electrostatic potential to identify perturbation resistant regions, generated by so-called electrostatic “hot-spots”. Distributions of electrostatic similarity based on families of perturbed structures illustrate the presence of electrostatic “hot-spots” at the two functional sites of C3d, while the surface of CR2 lacks electrostatic “hot-spots” despite its excessively positive nature. We propose that the electrostatic “hot-spots” of C3d have evolved to optimize its dual-functionality (covalently attaching to pathogen surfaces and interaction with CR2), which are both necessary for the formation B-cell co-receptor complexes. Comparison of the perturbation resistance of the electrostatic character of the homologues of C3d suggests that there was an emergence of a new role of electrostatics, and a transition in the function of C3d, after the divergence of jawless fish. PMID:23300422

Comparative genomic analysis of the Tribolium immune system

PubMed Central

Zou, Zhen; Evans, Jay D; Lu, Zhiqiang; Zhao, Picheng; Williams, Michael; Sumathipala, Niranji; Hetru, Charles; Hultmark, Dan; Jiang, Haobo

2007-01-01

Background Tribolium castaneum is a species of Coleoptera, the largest and most diverse order of all eukaryotes. Components of the innate immune system are hardly known in this insect, which is in a key phylogenetic position to inform us about genetic innovations accompanying the evolution of holometabolous insects. We have annotated immunity-related genes and compared them with homologous molecules from other species. Results Around 300 candidate defense proteins are identified based on sequence similarity to homologs known to participate in immune responses. In most cases, paralog counts are lower than those of Drosophila melanogaster or Anopheles gambiae but are substantially higher than those of Apis mellifera. The genome contains probable orthologs for nearly all members of the Toll, IMD, and JAK/STAT pathways. While total numbers of the clip-domain serine proteinases are approximately equal in the fly (29), mosquito (32) and beetle (30), lineage-specific expansion of the family is discovered in all three species. Sixteen of the thirty-one serpin genes form a large cluster in a 50 kb region that resulted from extensive gene duplications. Among the nine Toll-like proteins, four are orthologous to Drosophila Toll. The presence of scavenger receptors and other related proteins indicates a role of cellular responses in the entire system. The structures of some antimicrobial peptides drastically differ from those in other orders of insects. Conclusion A framework of information on Tribolium immunity is established, which may serve as a stepping stone for future genetic analyses of defense responses in a nondrosophiline genetic model insect. PMID:17727709

Information analysis of immune and endocrine organs. Morphological changes in the course of infection.

PubMed

Avtandilov, G G; Barsukov, V S

1992-11-01

Morphological and morphometric studies were conducted into lymphoid and endocrine organs of 259 human adults and infants with pyoinflammatory diseases (PID) and of 300 experimental mice. Informative and correlation analyses of the data thus recorded provided evidence to the effect that in the course of an infection process adaptation and compensation responses were characterized by intensified exchange of information within the immune-endocrine system (IES). Septic courses of PID were found to be accompanied by impairment of inter-organ correlations, increase in information entropy and progressive structural disorganization of the IES.

[Effects of extremely high-frequency electromagnetic radiation on the immune system and systemic regulation of homeostasis].

PubMed

Lushnikov, K V; Gapeev, A B; Chemeris, N K

2002-01-01

Low-intensity of electromagnetic radiation of extremely high frequencies (EHF EMR) is effectively used in medical practice for diagnostics, prevention and treatment of a broad spectrum of diseases of different etiology. However, in spite of existence of many hypotheses about mechanisms of EHF EMR effects on the molecular and cellular levels of organization of living systems, there is not conception that could explain all diversity of the EHF-therapy effects from unified approach. In our opinion, the problem of determination of mechanisms of EHF EMR effects on living organism is divided into two basic tasks: first, determining subcellular structures which can receive radiation, and, second, studying physiological reactions of the organism which are caused by radiation. It is obviously, that investigation of functions of single cells and subcellular elements can not entirely explain therapeutic effects and mechanisms of EHF EMR influence on multicellular organism on the whole. Plenty of functional relationships between organs and systems of organs should be taken into account. In the present review, a realization of the EHF-therapy effects due to the influence on immune system functions and start of system mechanisms of maintenance of the homeostasis on the organism level is hypothesized. Potential targets for EHF EMR acception on the level of different systems of the organism are analysed. The material is formed so that functional relations between immune system and other regulatory systems (nervous and endocrine systems) are traced.

Structure of C3b reveals conformational changes that underlie complement activity.

PubMed

Janssen, Bert J C; Christodoulidou, Agni; McCarthy, Andrew; Lambris, John D; Gros, Piet

2006-11-09

Resistance to infection and clearance of cell debris in mammals depend on the activation of the complement system, which is an important component of innate and adaptive immunity. Central to the complement system is the activated form of C3, called C3b, which attaches covalently to target surfaces to amplify complement response, label cells for phagocytosis and stimulate the adaptive immune response. C3b consists of 1,560 amino-acid residues and has 12 domains. It binds various proteins and receptors to effect its functions. However, it is not known how C3 changes its conformation into C3b and thereby exposes its many binding sites. Here we present the crystal structure at 4-A resolution of the activated complement protein C3b and describe the conformational rearrangements of the 12 domains that take place upon proteolytic activation. In the activated form the thioester is fully exposed for covalent attachment to target surfaces and is more than 85 A away from the buried site in native C3 (ref. 5). Marked domain rearrangements in the alpha-chain present an altered molecular surface, exposing hidden and cryptic sites that are consistent with known putative binding sites of factor B and several complement regulators. The structural data indicate that the large conformational changes in the proteolytic activation and regulation of C3 take place mainly in the first conversion step, from C3 to C3b. These insights are important for the development of strategies to treat immune disorders that involve complement-mediated inflammation.

The cost of doing business: cost structure of electronic immunization registries.

PubMed

Fontanesi, John M; Flesher, Don S; De Guire, Michelle; Lieberthal, Allan; Holcomb, Kathy

2002-10-01

To predict the true cost of developing and maintaining an electronic immunization registry, and to set the framework for developing future cost-effective and cost-benefit analysis. Primary data collected at three immunization registries located in California, accounting for 90 percent of all immunization records in registries in the state during the study period. A parametric cost analysis compared registry development and maintenance expenditures to registry performance requirements. Data were collected at each registry through interviews, reviews of expenditure records, technical accomplishments development schedules, and immunization coverage rates. The cost of building immunization registries is predictable and independent of the hardware/software combination employed. The effort requires four man-years of technical effort or approximately $250,000 in 1998 dollars. Costs for maintaining a registry were approximately $5,100 per end user per three-year period. There is a predictable cost structure for both developing and maintaining immunization registries. The cost structure can be used as a framework for examining the cost-effectiveness and cost-benefits of registries. The greatest factor effecting improvement in coverage rates was ongoing, user-based administrative investment.

Specific β-Turns Precede PPIIL Structures Binding to Allele-Specific HLA-DRβ1* PBRs in Fully-Protective Malaria Vaccine Components

PubMed Central

Bermudez, Adriana; Alba, Martha P.; Vanegas, Magnolia; Patarroyo, Manuel A.; Patarroyo, Manuel E.

2018-01-01

The 3D structural analysis of 62 peptides derived from highly pathogenic Plasmodium falciparum malaria parasite proteins involved in host cell invasion led to finding a striking association between particular β-turn types located in the N-terminal peripheral flanking residue region (preceding the polyproline II left-handed structures fitting into the HLA-DRβ* allele family) and modified immune protection-inducing protein structure induced long-lasting protective immunity. This is the first time association between two different secondary structures associated with a specific immunological function has been described: full, long-lasting protective immunity. PMID:29682500

Specific β-turns precede PPIIL structures binding to allele-specific HLA-DRβ1* PBRs in fully-protective malaria vaccine components

NASA Astrophysics Data System (ADS)

Bermudez, Adriana; Alba, Martha P.; Vanegas, Magnolia; Patarroyo, Manuel A.; Patarroyo, Manuel E.

2018-04-01

The 3D structural analysis of 62 peptides derived from highly pathogenic Plasmodium falciparum malaria parasite proteins involved in host cell invasion led to finding a striking association between particular β-turn types located in the N-terminal peripheral flanking residue region (preceding the polyproline II left-handed structures fitting into the HLA-DRβ* allele family) and modified immune protection-inducing protein structure induced long-lasting protective immunity. This is the first time association between two different secondary structures associated with a specific immunological function has been described: full, long-lasting protective immunity.

Construction of recombinant Mip-FlaA dominant epitope vaccine against Legionella pneumophila and evaluation of the immunogenicity and protective immunity.

PubMed

He, Jinlei; Zhang, Junrong; He, Yanxia; Huang, Fan; Li, Jiao; Chen, Qiwei; Chen, Dali; Chen, Jianping

2016-02-01

Legionnaires' disease, a kind of systemic disease with pneumonia as the main manifestation, is caused by Legionella pneumophila (L. pneumophila). In order to prevent the disease, we optimized Mip and FlaA, the virulence factors of L. pneumophila, to design recombinant Mip-FlaA dominant epitope vaccine against the pathogen. Firstly, the coding sequences of mip and flaA were optimized by DNAStar software and Expasy protein analysis system, and then, the tertiary structure and function of recombinant Mip-FlaA were predicted by PHYRE2 Protein Fold Recognition Server. After that, the optimized mip, flaA and mip-flaA were cloned, expressed and purified, and the proteins were used as dominant epitope vaccines to immunize BABL/c mice. Moreover, the IgG titers, histological changes in lung and the level of TNF-α, IFN-γ, IL-6 and IL-1β were detected to reflect the immunogenicity and protective immunity of the vaccines. The results of SDS-PAGE and Western blot proved the recombinant Mip-FlaA was successfully expressed. ELISA results of IgG titers and these cytokines showed Mip-FlaA group was capable to induce the strongest immune response, compared to PBS, Mip and FlaA groups. In addition, histopathology analysis demonstrated the mice immunized with Mip-FlaA showed better immune protection. Therefore, the work indicated that the above-described biological tools were useful in optimization of epitope vaccine. Antigenic characterization and immune protection of recombinant Mip-FlaA would be of great value in understanding the immunopathogenesis of the disease and in developing possible vaccine against the pathogen.

An effective immunization strategy for airborne epidemics in modular and hierarchical social contact network

NASA Astrophysics Data System (ADS)

Song, Zhichao; Ge, Yuanzheng; Luo, Lei; Duan, Hong; Qiu, Xiaogang

2015-12-01

Social contact between individuals is the chief factor for airborne epidemic transmission among the crowd. Social contact networks, which describe the contact relationships among individuals, always exhibit overlapping qualities of communities, hierarchical structure and spatial-correlated. We find that traditional global targeted immunization strategy would lose its superiority in controlling the epidemic propagation in the social contact networks with modular and hierarchical structure. Therefore, we propose a hierarchical targeted immunization strategy to settle this problem. In this novel strategy, importance of the hierarchical structure is considered. Transmission control experiments of influenza H1N1 are carried out based on a modular and hierarchical network model. Results obtained indicate that hierarchical structure of the network is more critical than the degrees of the immunized targets and the modular network layer is the most important for the epidemic propagation control. Finally, the efficacy and stability of this novel immunization strategy have been validated as well.

Stability of Bovine viral diarrhea virus 1 nucleic acid in fetal bovine samples stored under different conditions

USDA-ARS?s Scientific Manuscript database

Infection of pregnant cattle with bovine viral diarrhea viruses can result in reproductive disease that includes fetal reabsorption, mummification, abortion, still births, congenital defects affecting structural, neural, reproductive and immune systems and the birth of calves persistently infected w...

Phenotypic, ultra-structural and functional characterization of bovine peripheral blood dendritic cell subsets

USDA-ARS?s Scientific Manuscript database

Dendritic cells (DC) are multifunctional cells that bridge the gap between innate and adaptive immune systems. In bovine, significant information is lacking on the precise identity and role of peripheral blood DC subsets. In this study, we identify and characterize bovine peripheral blood DC subsets...

Production and regulation of functional amyloid curli fimbriae by Shiga toxin-producing Escherichia coli

USDA-ARS?s Scientific Manuscript database

Functional amyloid, in the form of adhesive fimbrial proteins termed curli, was first described in Salmonella and Escherichia coli. Curli fibers adhere to various host cells and structural proteins, interact with components of the host immune system, and participate in biofilm formation. Shiga toxin...

Vaginal type-II mucosa is an inductive site for primary CD8+ T-cell mucosal immunity

PubMed Central

Wang, Yichuan; Sui, Yongjun; Kato, Shingo; Hogg, Alison E.; Steel, Jason C.; Morris, John C.; Berzofsky, Jay A.

2014-01-01

The structured lymphoid tissues are considered the only inductive sites where primary T cell immune responses occur. The naïve T cells in structured lymphoid tissues, once being primed by antigen -bearing dendritic cells, differentiate into memory T cells and traffic back to the mucosal sites through the bloodstream. Contrary to this belief, here we show that the vaginal type-II mucosa itself, despite lack of structured lymphoid tissues, can act as an inductive site during primary CD8+ T cell immune responses. We provide evidence that the vaginal mucosa supports both the local immune priming of naïve CD8+ T cells and the local expansion of antigen-specific CD8+ T cells, thereby demonstrating a different paradigm for primary mucosal T cell immune induction. PMID:25600442

Immune allied genetic algorithm for Bayesian network structure learning

NASA Astrophysics Data System (ADS)

Song, Qin; Lin, Feng; Sun, Wei; Chang, KC

2012-06-01

Bayesian network (BN) structure learning is a NP-hard problem. In this paper, we present an improved approach to enhance efficiency of BN structure learning. To avoid premature convergence in traditional single-group genetic algorithm (GA), we propose an immune allied genetic algorithm (IAGA) in which the multiple-population and allied strategy are introduced. Moreover, in the algorithm, we apply prior knowledge by injecting immune operator to individuals which can effectively prevent degeneration. To illustrate the effectiveness of the proposed technique, we present some experimental results.

Protective efficacy of a novel alpha hemolysin subunit vaccine (AT62) against Staphylococcus aureus skin and soft tissue infections.

PubMed

Adhikari, Rajan P; Thompson, Christopher D; Aman, M Javad; Lee, Jean C

2016-12-07

Alpha hemolysin (Hla) is a pore-forming toxin produced by most Staphylococcus aureus isolates. Hla is reported to play a key role in the pathogenesis of staphylococcal infections, such as skin and soft tissue infection, pneumonia, and lethal peritonitis. This study makes use of a novel recombinant subunit vaccine candidate (AT62) that was rationally designed based on the Hla heptameric crystal structure. AT62 comprises a critical structural domain at the N terminus of Hla, and it has no inherent toxic properties. We evaluated the efficacy of AT62 in protection against surgical wound infection and skin and soft tissue infection. Mice were vaccinated on days 0, 14, and 28 with 20μg AT62 or bovine serum albumin (BSA) mixed with Sigma adjuvant system®. Mice immunized with AT62 produced a robust antibody response against native Hla. In the surgical wound infection model, mice immunized with AT62 and challenged with a USA300 S. aureus strain showed a significantly reduced bacterial burden in the infected tissue compared to animals given BSA. Similarly, mice passively immunized with rabbit IgG to AT62 showed reduced wound infection and tissue damage. Subcutaneous abscess formation was not prevented by immunization with AT62. However, in a skin necrosis infection model, immunization with the AT62 vaccine resulted in smaller lesions and reduced mouse weight loss compared to controls. Although AT62 immunization reduced tissue necrosis, it did not reduce the bacterial burdens in the lesions compared to controls. Our data indicate that AT62 may be a valuable component of a multivalent vaccine against S. aureus. Copyright © 2016 Elsevier Ltd. All rights reserved.

Testicular defense systems: immune privilege and innate immunity

PubMed Central

Zhao, Shutao; Zhu, Weiwei; Xue, Shepu; Han, Daishu

2014-01-01

The mammalian testis possesses a special immunological environment because of its properties of remarkable immune privilege and effective local innate immunity. Testicular immune privilege protects immunogenic germ cells from systemic immune attack, and local innate immunity is important in preventing testicular microbial infections. The breakdown of local testicular immune homeostasis may lead to orchitis, an etiological factor of male infertility. The mechanisms underlying testicular immune privilege have been investigated for a long time. Increasing evidence shows that both a local immunosuppressive milieu and systemic immune tolerance are involved in maintaining testicular immune privilege status. The mechanisms underlying testicular innate immunity are emerging based on the investigation of the pattern recognition receptor-mediated innate immune response in testicular cells. This review summarizes our current understanding of testicular defense mechanisms and identifies topics that merit further investigation. PMID:24954222

Natural evolution, disease, and localization in the immune system

NASA Astrophysics Data System (ADS)

Deem, Michael

2004-03-01

Adaptive vertebrate immune system is a wonder of modern evolution. Under most circumstances, the dynamics of the immune system is well-matched to the dynamics of pathogen growth during a typical infection. Some pathogens, however, have evolved escape mechanisms that interact in subtle ways with the immune system dynamics. In addition, negative interactions the immune system, which has evolved over 400 000 000 years, and vaccination,which has been practiced for only 200 years, are possible. For example,vaccination against the flu can actually increase susceptibility to the flu in the next year. As another example, vaccination against one of the four strains of dengue fever typically increases susceptibility against the other three strains. Immunodominance also arises in the immune system control of nascent tumors--the immune system recognizes only a small subset of the tumor specific antigens, and the rest are free to grow and cause tumor growth. In this talk, I present a physical theory of original antigenic sin and immunodominance. How localization in the immune system leads to the observed phenomena is discussed. 1) M. W. Deem and H. Y. Lee, ``Sequence Space Localization in the Immune System Response to Vaccination and Disease,'' Phys. Rev. Lett. 91 (2003) 068101

Extended Surface for Membrane Association in Zika Virus NS1 Structure

PubMed Central

Brown, W. Clay; Akey, David L.; Konwerski, Jamie; Tarrasch, Jeffrey T.; Skiniotis, Georgios; Kuhn, Richard J.; Smith, Janet L.

2018-01-01

The Zika virus, which is implicated in an increase in neonatal microcephaly and Guillain-Barré syndrome, has spread rapidly through tropical regions of the world. The virulence protein NS1 functions in genome replication and host immune system modulation. Here we report the crystal structure of full-length Zika virus NS1, revealing an elongated hydrophobic surface for membrane association and a polar surface that varies substantially among flaviviruses. PMID:27455458

Structure-activity relationships in beta-defensin peptides.

PubMed

Taylor, Karen; Barran, Perdita E; Dorin, Julia R

2008-01-01

The beta-defensins comprise a large family of small cationic antimicrobial peptides widely distributed in plants, mammals and insects. These cysteine rich peptides display multifunctional properties with implications as potential therapeutic agents. Recent research has highlighted their role in both the innate and adaptive immune systems as well as being novel melanocortin ligands. Studies investigating structure and function provide an insight into the molecular basis of their immunological properties. (c) 2007 Wiley Periodicals, Inc.

Role of the immune system in regeneration and its dynamic interplay with adult stem cells.

PubMed

Abnave, Prasad; Ghigo, Eric

2018-04-09

The immune system plays an indispensable role in the process of tissue regeneration following damage as well as during homeostasis. Inflammation and immune cell recruitment are signs of early onset injury. At the wound site, immune cells not only help to clear debris but also secrete numerous signalling molecules that induce appropriate cell proliferation and differentiation programmes essential for successful regeneration. However, the immune system does not always perform a complementary role in regeneration and several reports have suggested that increased inflammation can inhibit the regeneration process. Successful regeneration requires a balanced immune cell response, with the recruitment of accurately polarised immune cells in an appropriate quantity. The regulatory interactions of the immune system with regeneration are not unidirectional. Stem cells, as key players in regeneration, can also modulate the immune system in several ways to facilitate regeneration. In this review, we will focus on recent research demonstrating the key role of immune system in the regeneration process as well as the immunomodulatory effects of stem cells. Finally, we propose that research investigating the interplay between the immune system and stem cells within highly regenerating animals can benefit the identification of the key interactions and molecules required for successful regeneration. Copyright © 2018 Elsevier Ltd. All rights reserved.

Triggering the adaptive immune system with commensal gut bacteria protects against insulin resistance and dysglycemia.

PubMed

Pomié, Céline; Blasco-Baque, Vincent; Klopp, Pascale; Nicolas, Simon; Waget, Aurélie; Loubières, Pascale; Azalbert, Vincent; Puel, Anthony; Lopez, Frédéric; Dray, Cédric; Valet, Philippe; Lelouvier, Benjamin; Servant, Florence; Courtney, Michael; Amar, Jacques; Burcelin, Rémy; Garidou, Lucile

2016-06-01

To demonstrate that glycemia and insulin resistance are controlled by a mechanism involving the adaptive immune system and gut microbiota crosstalk. We triggered the immune system with microbial extracts specifically from the intestinal ileum contents of HFD-diabetic mice by the process of immunization. 35 days later, immunized mice were fed a HFD for up to two months in order to challenge the development of metabolic features. The immune responses were quantified. Eventually, adoptive transfer of immune cells from the microbiota-immunized mice to naïve mice was performed to demonstrate the causality of the microbiota-stimulated adaptive immune system on the development of metabolic disease. The gut microbiota of the immunized HFD-fed mice was characterized in order to demonstrate whether the manipulation of the microbiota to immune system interaction reverses the causal deleterious effect of gut microbiota dysbiosis on metabolic disease. Subcutaneous injection (immunization procedure) of ileum microbial extracts prevented hyperglycemia and insulin resistance in a dose-dependent manner in response to a HFD. The immunization enhanced the proliferation of CD4 and CD8 T cells in lymphoid organs, also increased cytokine production and antibody secretion. As a mechanism explaining the metabolic improvement, the immunization procedure reversed gut microbiota dysbiosis. Finally, adoptive transfer of immune cells from immunized mice improved metabolic features in response to HFD. Glycemia and insulin sensitivity can be regulated by triggering the adaptive immunity to microbiota interaction. This reduces the gut microbiota dysbiosis induced by a fat-enriched diet.

From birth to ‘immuno-health’, allergies and enterocolitis

PubMed Central

Houghteling, Pearl D.; Walker, W. Allan

2015-01-01

Microbial signals stimulate development and maintenance of the neonatal immune system. The process begins in utero, with limited exposure to microbes in the intrauterine environment, as well as maternal immune signals priming the developing immune system. After birth and initial colonization, the immune system must be able to activate against pathogens, but also achieve oral tolerance of food and resident gut microbes. Through microbial signals and appropriate nutrition, the immune system is able to achieve homeostasis. Major challenges to successful colonization and immune system regulation include abnormal microbial inoculi (cesarean section, hygiene) and antibiotics. When normal colonization is interrupted, dysbiosis occurs. This imbalance of microbes and subsequently of the immune system can result in allergic diseases, asthma or necrotizing enterocolitis. Probiotics and probiotic-derived therapies represent an exciting avenue to replete the population of commensal microbes and to prevent the immune-mediated sequelae of dysbiosis. PMID:26447970

The Major Histocompatibility Complex and Autism Spectrum Disorder

PubMed Central

Needleman, Leigh A.; McAllister, A. Kimberley

2015-01-01

Autism spectrum disorder (ASD) is a complex disorder that appears to be caused by interactions between genetic changes and environmental insults during early development. A wide range of factors have been linked to the onset of ASD, but recently both genetic associations and environmental factors point to a central role for immune- related genes and immune responses to environmental stimuli. Specifically, many of the proteins encoded by the major histocompatibility complex (MHC) play a vital role in the formation, refinement, maintenance, and plasticity of the brain. Manipulations of levels of MHC molecules have illustrated how disrupted MHC signaling can significantly alter brain connectivity and function. Thus, an emerging hypothesis in our field is that disruptions in MHC expression in the developing brain caused by mutations and/or immune dysregulation may contribute to the altered brain connectivity and function characteristic of ASD. This review provides an overview of the structure and function of the three classes of MHC molecules in the immune system, healthy brain, and their possible involvement in ASD. PMID:22760919

AB toxins: a paradigm switch from deadly to desirable.

PubMed

Odumosu, Oludare; Nicholas, Dequina; Yano, Hiroshi; Langridge, William

2010-07-01

To ensure their survival, a number of bacterial and plant species have evolved a common strategy to capture energy from other biological systems. Being imperfect pathogens, organisms synthesizing multi-subunit AB toxins are responsible for the mortality of millions of people and animals annually. Vaccination against these organisms and their toxins has proved rather ineffective in providing long-term protection from disease. In response to the debilitating effects of AB toxins on epithelial cells of the digestive mucosa, mechanisms underlying toxin immunomodulation of immune responses have become the focus of increasing experimentation. The results of these studies reveal that AB toxins may have a beneficial application as adjuvants for the enhancement of immune protection against infection and autoimmunity. Here, we examine similarities and differences in the structure and function of bacterial and plant AB toxins that underlie their toxicity and their exceptional properties as immunomodulators for stimulating immune responses against infectious disease and for immune suppression of organ-specific autoimmunity.

AB Toxins: A Paradigm Switch from Deadly to Desirable

PubMed Central

Odumosu, Oludare; Nicholas, Dequina; Yano, Hiroshi; Langridge, William

2010-01-01

To ensure their survival, a number of bacterial and plant species have evolved a common strategy to capture energy from other biological systems. Being imperfect pathogens, organisms synthesizing multi-subunit AB toxins are responsible for the mortality of millions of people and animals annually. Vaccination against these organisms and their toxins has proved rather ineffective in providing long-term protection from disease. In response to the debilitating effects of AB toxins on epithelial cells of the digestive mucosa, mechanisms underlying toxin immunomodulation of immune responses have become the focus of increasing experimentation. The results of these studies reveal that AB toxins may have a beneficial application as adjuvants for the enhancement of immune protection against infection and autoimmunity. Here, we examine similarities and differences in the structure and function of bacterial and plant AB toxins that underlie their toxicity and their exceptional properties as immunomodulators for stimulating immune responses against infectious disease and for immune suppression of organ-specific autoimmunity. PMID:22069653

Immunization with Outer Membrane Vesicles Displaying Designer Glycotopes Yields Class-Switched, Glycan-Specific Antibodies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valentine, Jenny L.; Chen, Linxiao; Perregaux, Emily C.

The development of antibodies against specific glycan epitopes poses a significant challenge due to difficulties obtaining desired glycans at sufficient quantity and purity, and the fact that glycans are usually weakly immunogenic. To address this challenge, we leveraged the potent immunostimulatory activity of bacterial outer membrane vesicles (OMVs) to deliver designer glycan epitopes to the immune system. This approach involved heterologous expression of two clinically important glycans, namely polysialic acid (PSA) and Thomsen-Friedenreich antigen (T antigen) in hypervesiculating strains of non-pathogenic Escherichia coli. The resulting glycOMVs displayed structural mimics of PSA or T antigen on their surfaces, and induced highmore » titers of glycan-specific IgG antibodies following immunization in mice. In the case of PSA glycOMVs, serum antibodies potently killed Neisseria meningitidis serogroup B (MenB), whose outer capsule is PSA, in a serum bactericidal assay. These findings demonstrate the potential of glycOMVs for inducing class-switched, humoral immune responses against glycan antigens.« less

[Immune response in cervical cancer. Strategies for the development of therapeutic vaccines].

PubMed

Mora-García, María Lourdes; Monroy-García, Alberto

2015-01-01

High-risk human papillomaviruses (HR-HPV), as HPV-16, evade immune recognition through the inactivation of cells of the innate immune response. HPV-16 E6 and E7 genes down-regulate type I interferon response. They do not produce viremia or cell death; therefore, they do not cause inflammation or damage signal that alerts the immune system. Virus-like particles (VLPs), consisting of structural proteins (L1 and L2) of the main HR-HPV types that infect the genitourinary tract, are the most effective prophylactic vaccines against HR-HPV infection. While for the high grade neoplastic lesions, therapeutic vaccines based on viral vectors, peptides, DNA or complete HR-HPV E6 and E7 proteins as antigens, have had limited effectiveness. Chimeric virus-like particles (cVLPs) that carry immunogenic peptides derived from E6 and E7 viral proteins, capable to induce activation of specific cytotoxic T lymphocytes, emerge as an important alternative to provide prophylactic and therapeutic activity against HR-HPV infection and cervical cancer.

Immunization with Outer Membrane Vesicles Displaying Designer Glycotopes Yields Class-Switched, Glycan-Specific Antibodies

DOE PAGES

Valentine, Jenny L.; Chen, Linxiao; Perregaux, Emily C.; ...

2016-06-23

The development of antibodies against specific glycan epitopes poses a significant challenge due to difficulties obtaining desired glycans at sufficient quantity and purity, and the fact that glycans are usually weakly immunogenic. To address this challenge, we leveraged the potent immunostimulatory activity of bacterial outer membrane vesicles (OMVs) to deliver designer glycan epitopes to the immune system. This approach involved heterologous expression of two clinically important glycans, namely polysialic acid (PSA) and Thomsen-Friedenreich antigen (T antigen) in hypervesiculating strains of non-pathogenic Escherichia coli. The resulting glycOMVs displayed structural mimics of PSA or T antigen on their surfaces, and induced highmore » titers of glycan-specific IgG antibodies following immunization in mice. In the case of PSA glycOMVs, serum antibodies potently killed Neisseria meningitidis serogroup B (MenB), whose outer capsule is PSA, in a serum bactericidal assay. These findings demonstrate the potential of glycOMVs for inducing class-switched, humoral immune responses against glycan antigens.« less

Microbiota regulate the development and function of the immune cells.

PubMed

Yu, Qing; Jia, Anna; Li, Yan; Bi, Yujing; Liu, Guangwei

2018-03-04

Microbiota is a group of microbes coexisting and co-evolving with the immune system in the host body for millions of years. There are mutual interaction between microbiota and the immune system. Immune cells can shape the populations of microbiota in the gut of animals and humans, and the presence of microbiota and the microbial products can regulate the development and function of the immune cells in the host. Although microbiota resides mainly at the mucosa, the effect of microbiota on the immune system can be both local at the mucosa and systemic through the whole body. At the mucosal sites, the presences of microbiota and microbial products have a direct effect on the immune cells. Microbiota induces production of effectors from immune cells, such as cytokines and inflammatory factors, influencing the further development and function of the immune cells. Experimental data have shown that microbial products can influence the activity of some key factors in signaling pathways. At the nonmucosal sites, such as the bone marrow, peripheral lymph nodes, and spleen, microbiota can also regulate the development and function of the immune cells via several mechanisms in mice, such as introduction of chromatin-level changes through histone acetylation and DNA methylation. Given the important effect of microbiota on the immune system, many immunotherapies that are mediated by immune system rely on gut microbiota. Thus, the study of how microbiota influences immune system bring a potential therapy prospect in preventing and treating diseases.

The role of the immune system in Alzheimer disease: Etiology and treatment.

PubMed

Jevtic, Stefan; Sengar, Ameet S; Salter, Michael W; McLaurin, JoAnne

2017-11-01

The immune system is now considered a major factor in Alzheimer Disease (AD). This review seeks to demonstrate how various aspects of the immune system, both in the brain and peripherally, interact to contribute to AD. We highlight classical nervous system immune components, such as complement and microglia, as well as novel aspects of the peripheral immune system that can influence disease, such as monocytes and lymphocytes. By detailing the roles of various immune cells in AD, we summarize an emerging perspective for disease etiology and future therapeutic targets. Copyright © 2017. Published by Elsevier B.V.

Primary processing of CRISPR RNA by the endonuclease Cas6 in Staphylococcus epidermidis.

PubMed

Wakefield, Noelle; Rajan, Rakhi; Sontheimer, Erik J

2015-10-07

In many bacteria and archaea, an adaptive immune system (CRISPR-Cas) provides immunity against foreign genetic elements. This system uses CRISPR RNAs (crRNAs) derived from the CRISPR array, along with CRISPR-associated (Cas) proteins, to target foreign nucleic acids. In most CRISPR systems, endonucleolytic processing of crRNA precursors (pre-crRNAs) is essential for the pathway. Here we study the Cas6 endonuclease responsible for crRNA processing in the Type III-A CRISPR-Cas system from Staphylococcus epidermidis RP62a, a model for Type III-A CRISPR-Cas systems, and define substrate requirements for SeCas6 activity. We find that SeCas6 is necessary and sufficient for full-length crRNA biogenesis in vitro, and that it relies on both sequence and stem-loop structure in the 3' half of the CRISPR repeat for recognition and processing. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

The Neuromodulation of the Intestinal Immune System and Its Relevance in Inflammatory Bowel Disease.

PubMed

Di Giovangiulio, Martina; Verheijden, Simon; Bosmans, Goele; Stakenborg, Nathalie; Boeckxstaens, Guy E; Matteoli, Gianluca

2015-01-01

One of the main tasks of the immune system is to discriminate and appropriately react to "danger" or "non-danger" signals. This is crucial in the gastrointestinal tract, where the immune system is confronted with a myriad of food antigens and symbiotic microflora that are in constant contact with the mucosa, in addition to any potential pathogens. This large number of antigens and commensal microflora, which are essential for providing vital nutrients, must be tolerated by the intestinal immune system to prevent aberrant inflammation. Hence, the balance between immune activation versus tolerance should be tightly regulated to maintain intestinal homeostasis and to prevent immune activation indiscriminately against all luminal antigens. Loss of this delicate equilibrium can lead to chronic activation of the intestinal immune response resulting in intestinal disorders, such as inflammatory bowel diseases (IBD). In order to maintain homeostasis, the immune system has evolved diverse regulatory strategies including additional non-immunological actors able to control the immune response. Accumulating evidence strongly indicates a bidirectional link between the two systems in which the brain modulates the immune response via the detection of circulating cytokines and via direct afferent input from sensory fibers and from enteric neurons. In the current review, we will highlight the most recent findings regarding the cross-talk between the nervous system and the mucosal immune system and will discuss the potential use of these neuronal circuits and neuromediators as novel therapeutic tools to reestablish immune tolerance and treat intestinal chronic inflammation.

Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer.

PubMed

Marelli, Giulia; Howells, Anwen; Lemoine, Nicholas R; Wang, Yaohe

2018-01-01

Oncolytic viral therapy is a new promising strategy against cancer. Oncolytic viruses (OVs) can replicate in cancer cells but not in normal cells, leading to lysis of the tumor mass. Beside this primary effect, OVs can also stimulate the immune system. Tumors are an immuno-suppressive environment in which the immune system is silenced in order to avoid the immune response against cancer cells. The delivery of OVs into the tumor wakes up the immune system so that it can facilitate a strong and durable response against the tumor itself. Both innate and adaptive immune responses contribute to this process, producing an immune response against tumor antigens and facilitating immunological memory. However, viruses are recognized by the immune system as pathogens and the consequent anti-viral response could represent a big hurdle for OVs. Finding a balance between anti-tumor and anti-viral immunity is, under this new light, a priority for researchers. In this review, we provide an overview of the various ways in which different components of the immune system can be allied with OVs. We have analyzed the different immune responses in order to highlight the new and promising perspectives leading to increased anti-tumor response and decreased immune reaction to the OVs.

Diffuse endocrine system, neuroendocrine tumors and immunity: what's new?

PubMed

Ameri, Pietro; Ferone, Diego

2012-01-01

During the last two decades, research into the modulation of immunity by the neuroendocrine system has flourished, unravelling significant effects of several neuropeptides, including somatostatin (SRIH), and especially cortistatin (CST), on immune cells. Scientists have learnt that the diffuse neuroendocrine system can regulate the immune system at all its levels: innate immunity, adaptive immunity, and maintenance of immune tolerance. Compelling studies with animal models have demonstrated that some neuropeptides may be effective in treating inflammatory disorders, such as sepsis, and T helper 1-driven autoimmune diseases, like Crohn's disease and rheumatoid arthritis. Here, the latest findings concerning the neuroendocrine control of the immune system are discussed, with emphasis on SRIH and CST. The second part of the review deals with the immune response to neuroendocrine tumors (NETs). The anti-NET immune response has been described in the last years and it is still being characterized, similarly to what is happening for several other types of cancer. In parallel with investigations addressing the mechanisms by which the immune system contrasts NET growth and spreading, ground-breaking clinical trials of dendritic cell vaccination as immunotherapy for metastatic NETs have shown in principle that the immune reaction to NETs can be exploited for treatment. Copyright © 2012 S. Karger AG, Basel.

Coevolution of yeast mannan digestion: Convergence of the civilized human diet, distal gut microbiome, and host immunity

PubMed Central

Abbott, D Wade; Martens, Eric C; Gilbert, Harry J; Cuskin, Fiona; Lowe, Elisabeth C

2015-01-01

The complex carbohydrates accessible to the distal gut microbiota (DGM) are key drivers in determining the structure of this ecosystem. Typically, plant cell wall polysaccharides and recalcitrant starch (i.e. dietary fiber), in addition to host glycans are considered the primary nutrients for the DGM; however, we recently demonstrated that α-mannans, highly branched polysaccharides that decorate the surface of yeast, are also nutrients for several members of Bacteroides spp. This relationship suggests that the advent of yeast in contemporary food technologies and the colonization of the intestine by endogenous fungi have roles in microbiome structure and function. Here we discuss the process of yeast mannan metabolism, and the intersection between various sources of intestinal fungi and their roles in recognition by the host innate immune system. PMID:26440374

The immunological capacity in the larvae of Pacific oyster Crassostrea gigas.

PubMed

Song, Xiaorui; Wang, Hao; Xin, Lusheng; Xu, Jiachao; Jia, Zhihao; Wang, Lingling; Song, Linsheng

2016-02-01

As the immune system has not fully developed during early developmental stages, bivalve larvae are more susceptible for pathogens, which frequently leads to the significant mortality in hatcheries. In the present study, the development of immune system and its response against bacteria challenge were investigated in order to characterize the repertoire of immunological capacity of Pacific oyster Crassostrea gigas during the ontogenesis. The phagocytosis was firstly observed in the early D-veliger larvae (17 hpf), especially in their velum site, which indicated the appearance of functional hemocytes during early D-veliger larvae stage. The whole-mount immunofluorescence assay of three pattern recognition receptors (integrin β-1, caspase-3 and C-type lectin 3) and one immune effector gene (IL17-5) was performed in blastula, early D-veliger and umbo larvae, suggested that velum and digestive gland were the potential sites of immune system in the larvae. The lowest activities of antioxidant enzymes (superoxide dismutase and catalase) and hydrolytic enzyme (lysozyme), as well as descended expression levels of 12 immune genes at the transition between embryogenesis and planktonic, indicated that the larvae at hatching (9 hpf) were in hypo-immunity. While the ascending activities of enzymes and expression levels of seven immune genes during the trochophore stage (15 hpf) suggested the initiation of immune system. The steadily increasing trend of all the 12 candidate genes at the early umbo larvae (120 h) hinted that the immune system was well developed at this stage. After bacterial challenge, some immune recognition (TLR4) and immune effector (IL17-5 and defh2) genes were activated in blastula stage (4 hpf), and other immune genes were up regulated in D-veliger larvae, indicating that the zygotic immune system could respond earlier against the bacterial challenge during its development. These results indicated that the cellular and humoral immune components appeared at trochophore stage, and the cellular immune system was activated with its occurrence, while the humoral immune system executed until the early umbo larval stage. The immune system emerged earlier to aid larvae in defending bacterial challenge during the early stages of oyster development. Copyright © 2016 Elsevier Ltd. All rights reserved.

Tertiary Lymphoid Structure-Associated B Cells are Key Players in Anti-Tumor Immunity

PubMed Central

Germain, Claire; Gnjatic, Sacha; Dieu-Nosjean, Marie-Caroline

2015-01-01

It is now admitted that the immune system plays a major role in tumor control. Besides the existence of tumor-specific T cells and B cells, many studies have demonstrated that high numbers of tumor-infiltrating lymphocytes are associated with good clinical outcome. In addition, not only the density but also the organization of tumor-infiltrating immune cells has been shown to determine patient survival. Indeed, more and more studies describe the development within the tumor microenvironment of tertiary lymphoid structures (TLS), whose presence has a positive impact on tumor prognosis. TLS are transient ectopic lymphoid aggregates displaying the same organization and functionality as canonical secondary lymphoid organs, with T-cell-rich and B-cell-rich areas that are sites for the differentiation of effector and memory T cells and B cells. However, factors favoring the emergence of such structures within tumors still need to be fully characterized. In this review, we survey the state of the art of what is known about the general organization, induction, and functionality of TLS during chronic inflammation, and more especially in cancer, with a particular focus on the B-cell compartment. We detail the role played by TLS B cells in anti-tumor immunity, both as antigen-presenting cells and tumor antigen-specific antibody-secreting cells, and raise the question of the capacity of chemotherapeutic and immunotherapeutic agents to induce the development of TLS within tumors. Finally, we explore how to take advantage of our knowledge on TLS B cells to develop new therapeutic tools. PMID:25755654

Long-term immunologically competent human peripheral lymphoid tissue cultures in a 3D bioreactor

PubMed Central

Kuzin, Igor; Sun, Hongliang; Moshkani, Safiekhatoon; Feng, Changyong; Mantalaris, Athanasios; Wu, JH David; Bottaro, Andrea

2011-01-01

Peripheral lymphoid organs (PLOs), the primary sites of development of adaptive immune responses, display a complex structural organization reflecting separation of cellular subsets (e.g. T and B lymphocytes) and functional compartments which is critical for immune function. The generation of in vitro culture systems capable of recapitulating salient features of PLOs for experimental, biotechnological and clinical applications would be highly desirable, but has been hampered so far by the complexity of these systems. We have previously developed a three-dimensional bioreactor system for long-term, functional culture of human bone marrow cells on macroporous microspheres in a packed-bed bioreactor with frequent medium change. Here we adapt the same system for culture of human primary cells from PLOs (tonsil) in the absence of specific exogenous growth factors or activators. Cells in this system displayed higher viability over several weeks, and maintain population diversity and cell surface markers largely comparable to primary cells. Light microscopy showed cells organizing in large diverse clusters within the scaffold pores and presence of B cell-enriched areas. Strikingly, these cultures generated a significant number of antibody-producing B cells when challenged with a panel of diverse antigens, as expected from a lymphoid tissue. Thus the three-dimensional tonsil bioreactor culture system may serve as a useful model of PLOs by recapitulating their structural organization and function ex vivo. PMID:21309085

Long-term immunologically competent human peripheral lymphoid tissue cultures in a 3D bioreactor.

PubMed

Kuzin, Igor; Sun, Hongliang; Moshkani, Safiekhatoon; Feng, Changyong; Mantalaris, Athanasios; Wu, J H David; Bottaro, Andrea

2011-06-01

Peripheral lymphoid organs (PLOs), the primary sites of development of adaptive immune responses, display a complex structural organization reflecting separation of cellular subsets (e.g., T and B lymphocytes) and functional compartments which is critical for immune function. The generation of in vitro culture systems capable of recapitulating salient features of PLOs for experimental, biotechnological, and clinical applications would be highly desirable, but has been hampered so far by the complexity of these systems. We have previously developed a three-dimensional bioreactor system for long-term, functional culture of human bone marrow cells on macroporous microspheres in a packed-bed bioreactor with frequent medium change. Here we adapt the same system for culture of human primary cells from PLOs (tonsil) in the absence of specific exogenous growth factors or activators. Cells in this system displayed higher viability over several weeks, and maintain population diversity and cell surface markers largely comparable to primary cells. Light microscopy showed cells organizing in large diverse clusters within the scaffold pores and presence of B cell-enriched areas. Strikingly, these cultures generated a significant number of antibody-producing B cells when challenged with a panel of diverse antigens, as expected from a lymphoid tissue. Thus the three-dimensional tonsil bioreactor culture system may serve as a useful model of PLOs by recapitulating their structural organization and function ex vivo. Copyright © 2011 Wiley Periodicals, Inc.

Comparative Analysis of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) of Streptococcus thermophilus St-I and its Bacteriophage-Insensitive Mutants (BIM) Derivatives.

PubMed

Li, Wan; Bian, Xin; Evivie, Smith Etareri; Huo, Gui-Cheng

2016-09-01

The CRISPR-Cas (CRISPR together with CRISPR-associated proteins) modules are the adaptive immune system, acting as an adaptive and heritable immune system in bacteria and archaea. CRISPR-based immunity acts by integrating short virus sequences in the cell's CRISPR locus, allowing the cell to remember, recognize, and clear infections. In this study, the homology of CRISPRs sequence in BIMs (bacteriophage-insensitive mutants) of Streptococcus thermophilus St-I were analyzed. Secondary structures of the repeats and the PAMs (protospacer-associated motif) of each CRISPR locus were also predicted. Results showed that CRISPR1 has 27 repeat-spacer units, 5 of them had duplicates; CRISPR2 has one repeat-spacer unit; CRISPR3 has 28 repeat-spacer units. Only BIM1 had a new spacer acquisition in CRISPR3, while BIM2 and BIM3 had no new spacers' insertion, thus indicating that while most CRISPR1 were more active than CRISPR3, new spacer acquisition occurred just in CRSPR3 in some situations. These findings will help establish the foundation for the study of CRSPR-Cas systems in lactic acid bacteria.

Innate immune system and tissue regeneration in planarians: an area ripe for exploration.

PubMed

Peiris, T Harshani; Hoyer, Katrina K; Oviedo, Néstor J

2014-08-01

The immune system has been implicated as an important modulator of tissue regeneration. However, the mechanisms driving injury-induced immune response and tissue repair remain poorly understood. For over 200 years, planarians have been a classical model for studies on tissue regeneration, but the planarian immune system and its potential role in repair is largely unknown. We found through comparative genomic analysis and data mining that planarians contain many potential homologs of the innate immune system that are activated during injury and repair of adult tissues. These findings support the notion that the relationship between adult tissue repair and the immune system is an ancient feature of basal Bilateria. Further analysis of the planarian immune system during regeneration could potentially add to our understanding of how the innate immune system and inflammatory responses interplay with regenerative signals to induce scar-less tissue repair in the context of the adult organism. Copyright © 2014 Elsevier Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, C.; Coggill, P.; Bateman, A.

Many Gram-positive lactic acid bacteria (LAB) produce anti-bacterial peptides and small proteins called bacteriocins, which enable them to compete against other bacteria in the environment. These peptides fall structurally into three different classes, I, II, III, with class IIa being pediocin-like single entities and class IIb being two-peptide bacteriocins. Self-protective cognate immunity proteins are usually co-transcribed with these toxins. Several examples of cognates for IIa have already been solved structurally. Streptococcus pyogenes, closely related to LAB, is one of the most common human pathogens, so knowledge of how it competes against other LAB species is likely to prove invaluable. Wemore » have solved the crystal structure of the gene-product of locus Spy-2152 from S. pyogenes, (PDB: 2fu2), and found it to comprise an anti-parallel four-helix bundle that is structurally similar to other bacteriocin immunity proteins. Sequence analyses indicate this protein to be a possible immunity protein protective against class IIa or IIb bacteriocins. However, given that S. pyogenes appears to lack any IIa pediocin-like proteins but does possess class IIb bacteriocins, we suggest this protein confers immunity to IIb-like peptides. Combined structural, genomic and proteomic analyses have allowed the identification and in silico characterization of a new putative immunity protein from S. pyogenes, possibly the first structure of an immunity protein protective against potential class IIb two-peptide bacteriocins. We have named the two pairs of putative bacteriocins found in S. pyogenes pyogenecin 1, 2, 3 and 4.« less

Recent progress in elucidating the structure, function and evolution of disease resistance genes in plants.

PubMed

Liu, Jinling; Liu, Xionglun; Dai, Liangying; Wang, Guoliang

2007-09-01

Plants employ multifaceted mechanisms to fight with numerous pathogens in nature. Resistance (R) genes are the most effective weapons against pathogen invasion since they can specifically recognize the corresponding pathogen effectors or associated protein(s) to activate plant immune responses at the site of infection. Up to date, over 70 R genes have been isolated from various plant species. Most R proteins contain conserved motifs such as nucleotide-binding site (NBS), leucine-rich repeat (LRR), Toll-interleukin-1 receptor domain (TIR, homologous to cytoplasmic domains of the Drosophila Toll protein and the mammalian interleukin-1 receptor), coiled-coil (CC) or leucine zipper (LZ) structure and protein kinase domain (PK). Recent results indicate that these domains play significant roles in R protein interactions with effector proteins from pathogens and in activating signal transduction pathways involved in innate immunity. This review highlights an overview of the recent progress in elucidating the structure, function and evolution of the isolated R genes in different plant-pathogen interaction systems.

Structural Heterogeneity and Functional Domains of Murine Immunoglobulin G Fc Receptors

NASA Astrophysics Data System (ADS)

Ravetch, Jeffrey V.; Luster, Andrew D.; Weinshank, Richard; Kochan, Jarema; Pavlovec, Amalia; Portnoy, Daniel A.; Hulmes, Jeffrey; Pan, Yu-Ching E.; Unkeless, Jay C.

1986-11-01

Binding of antibodies to effector cells by way of receptors to their constant regions (Fc receptors) is central to the pathway that leads to clearance of antigens by the immune system. The structure and function of this important class of receptors on immune cells is addressed through the molecular characterization of Fc receptors (FcR) specific for the murine immunoglobulin G isotype. Structural diversity is encoded by two genes that by alternative splicing result in expression of molecules with highly conserved extracellular domains and different transmembrane and intracytoplasmic domains. The proteins encoded by these genes are members of the immunoglobulin supergene family, most homologous to the major histocompatibility complex molecule Eβ. Functional reconstitution of ligand binding by transfection of individual FcR genes demonstrates that the requirements for ligand binding are encoded in a single gene. These studies demonstrate the molecular basis for the functional heterogeneity of FcR's, accounting for the possible transduction of different signals in response to a single ligand.

Group A Streptococcus produce pilus-like structures containing protective antigens and Lancefield T antigens.

PubMed

Mora, Marirosa; Bensi, Giuliano; Capo, Sabrina; Falugi, Fabiana; Zingaretti, Chiara; Manetti, Andrea G O; Maggi, Tiziana; Taddei, Anna Rita; Grandi, Guido; Telford, John L

2005-10-25

Although pili have long been recognized in Gram-negative pathogens as important virulence factors involved in adhesion and invasion, very little is known about extended surface organelles in Gram-positive pathogens. Here we report that Group A Streptococcus (GAS), a Gram-positive human-specific pathogen that causes pharyngitis, impetigo, invasive disease, necrotizing fasciitis, and autoimmune sequelae has long, surface-exposed, pilus-like structures composed of members of a family of extracellular matrix-binding proteins. We describe four variant pili and show that each is recognized by a specific serum of the Lancefield T-typing system, which has been used for over five decades to characterize GAS isolates. Furthermore, we show that immunization of mice with a combination of recombinant pilus proteins confers protection against mucosal challenge with virulent GAS bacteria. The data indicate that induction of a protective immune response against these structures may be a useful strategy for development of a vaccine against disease caused by GAS infection.

A review of the human vs. porcine female genital tract and associated immune system in the perspective of using minipigs as a model of human genital Chlamydia infection.

PubMed

Lorenzen, Emma; Follmann, Frank; Jungersen, Gregers; Agerholm, Jørgen S

2015-09-28

Sexually transmitted diseases constitute major health issues and their prevention and treatment continue to challenge the health care systems worldwide. Animal models are essential for a deeper understanding of the diseases and the development of safe and protective vaccines. Currently a good predictive non-rodent model is needed for the study of genital chlamydia in women. The pig has become an increasingly popular model for human diseases due to its close similarities to humans. The aim of this review is to compare the porcine and human female genital tract and associated immune system in the perspective of genital Chlamydia infection. The comparison of women and sows has shown that despite some gross anatomical differences, the structures and proportion of layers undergoing cyclic alterations are very similar. Reproductive hormonal cycles are closely related, only showing a slight difference in cycle length and source of luteolysing hormone. The epithelium and functional layers of the endometrium show similar cyclic changes. The immune system in pigs is very similar to that of humans, even though pigs have a higher percentage of CD4(+)/CD8(+) double positive T cells. The genital immune system is also very similar in terms of the cyclic fluctuations in the mucosal antibody levels, but differs slightly regarding immune cell infiltration in the genital mucosa - predominantly due to the influx of neutrophils in the porcine endometrium during estrus. The vaginal flora in Göttingen Minipigs is not dominated by lactobacilli as in humans. The vaginal pH is around 7 in Göttingen Minipigs, compared to the more acidic vaginal pH around 3.5-5 in women. This review reveals important similarities between the human and porcine female reproductive tracts and proposes the pig as an advantageous supplementary model of human genital Chlamydia infection.

Salmonella enterica Serovar Enteritidis Ghosts Carrying the Escherichia coli Heat-Labile Enterotoxin B Subunit Are Capable of Inducing Enhanced Protective Immune Responses

PubMed Central

Jawale, Chetan V.

2014-01-01

The Escherichia coli heat-labile enterotoxin B subunit (LTB) is a potent vaccine adjuvant. Salmonella enterica serovar Enteritidis ghosts carrying LTB (S. Enteritidis-LTB ghosts) were genetically constructed using a novel plasmid, pJHL187-LTB, designed for the coexpression of the LTB and E lysis proteins. S. Enteritidis-LTB ghosts were characterized using scanning electron microscopy to visualize their transmembrane tunnel structures. The expression of LTB in S. Enteritidis-LTB ghost preparations was confirmed by immunoblot and enzyme-linked immunosorbent assays. The parenteral adjuvant activity of LTB was demonstrated by immunizing chickens with either S. Enteritidis-LTB ghosts or S. Enteritidis ghosts. Chickens were intramuscularly primed at 5 weeks of age and subsequently boosted at 8 weeks of age. In total, 60 chickens were equally divided into three groups (n = 20 for each): group A, nonvaccinated control; group B, immunized with S. Enteritidis-LTB ghosts; and group C, immunized with S. Enteritidis ghosts. Compared with the nonimmunized chickens (group A), the immunized chickens (groups B and C) exhibited increased titers of plasma IgG and intestinal secretory IgA antibodies. The CD3+ CD4+ subpopulation of T cells was also significantly increased in both immunized groups. Among the immunized chickens, those in group B exhibited significantly increased titers of specific plasma IgG and intestinal secretory IgA (sIgA) antibodies compared with those in group C, indicating the immunomodulatory effects of the LTB adjuvant. Furthermore, both immunized groups exhibited decreased bacterial loads in their feces and internal organs. These results indicate that parenteral immunization with S. Enteritidis-LTB ghosts can stimulate superior induction of systemic and mucosal immune responses compared to immunization with S. Enteritidis ghosts alone, thus conferring efficient protection against salmonellosis. PMID:24671556

Cell adhesion and the immune system: a case study using earthworms.

PubMed

Cooper, E L; Cossarizza, A; Kauschke, E; Franceschi, C

1999-02-15

In the earthworm's immune system, cell adhesion, which occurs by putative receptors on leukocytes, is essential after recognition of self vs. non-self. Confrontation with foreign antigens is a normal event in the environment, replete with microbial pathogens that pose a threat to survival. To better understand what happens when an effector cell first recognizes a foreign target followed by its adhesion to it, isolated leukocytes, in sufficient quantities to be subjected to various analyses, have been extremely beneficial. In vitro approaches when accompanied by biochemical, immunological, and molecular technologies, have opened up new vistas concerning the immune response of earthworms and other invertebrates. The most recent discovery includes the preliminary identification of cell differentiation (CD) markers that play vital roles in recognitive and adhesive events. Certain leukocyte effectors show characteristics of natural killer (NK) cells that may act differently depending upon their source, whether autogeneic, allogeneic, xenogeneic, or expressed under normal or varying environmental conditions including exposure to xenobiotics. At the level of earthworm evolution, there is apparently a dissociation of phagocytosis from the process of killing by NK-like effectors. There are at least three future challenges. First, it is essential to determine the precise nature of the CD markers with respect to their molecular structure. Second, once their molecular and biochemical characteristics have been defined, the role of these markers in cellular and humoral mechanisms must be clarified in order to define effector cell products and resulting immune responses. Third, there is a need to differentiate between the several lytic factors that have been found in earthworms with respect to molecular structure, and biochemical and functional characterization.

[Cancer immunotherapy. Importance of overcoming immune suppression].

PubMed

Malvicini, Mariana; Puchulo, Guillermo; Matar, Pablo; Mazzolini, Guillermo

2010-01-01

Increasing evidence indicates that the immune system is involved in the control of tumor progression. Effective antitumor immune response depends on the interaction between several components of the immune system, including antigen-presenting cells and different T cell subsets. However, tumor cells develop a number of mechanisms to escape recognition and elimination by the immune system. In this review we discuss these mechanisms and address possible therapeutic approaches to overcome the immune suppression generated by tumors.

HIV-1 and hijacking of the host immune system: the current scenario.

PubMed

Imran, Muhammad; Manzoor, Sobia; Saalim, Muhammad; Resham, Saleha; Ashraf, Javed; Javed, Aneela; Waqar, Ahmed Bilal

2016-10-01

Human immunodeficiency virus (HIV) infection is a major health burden across the world which leads to the development of acquired immune deficiency syndrome (AIDS). This review article discusses the prevalence of HIV, its major routes of transmission, natural immunity, and evasion from the host immune system. HIV is mostly prevalent in Sub-Saharan Africa and low income countries. It is mostly transmitted by sharing syringe needles, blood transfusion, and sexual routes. The host immune system is categorized into three main types; the innate, the adaptive, and the intrinsic immune system. Regarding the innate immune system against HIV, the key players are mucosal membrane, dendritic cells (DCs), complement system, interferon, and host Micro RNAs. The major components of the adaptive immune system exploited by HIV are T cells mainly CD4+ T cells and B cells. The intrinsic immune system confronted by HIV involves (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) APOBEC3G, tripartite motif 5-α (TRIM5a), terherin, and (SAM-domain HD-domain containing protein) SAMHD1. HIV-1 efficiently interacts with the host immune system, exploits the host machinery, successfully replicates and transmits from one cell to another. Further research is required to explore evasion strategies of HIV to develop novel therapeutic approaches against HIV. © 2016 APMIS. Published by John Wiley & Sons Ltd.

Chlamydia trachomatis recombinant MOMP encapsulated in PLGA nanoparticles triggers primarily T helper 1 cellular and antibody immune responses in mice: a desirable candidate nanovaccine.

PubMed

Fairley, Stacie J; Singh, Shree R; Yilma, Abebayehu N; Waffo, Alain B; Subbarayan, Praseetha; Dixit, Saurabh; Taha, Murtada A; Cambridge, Chino D; Dennis, Vida A

2013-01-01

We recently demonstrated by in vitro experiments that PLGA (poly D, L-lactide-co-glycolide) potentiates T helper 1 (Th1) immune responses induced by a peptide derived from the recombinant major outer membrane protein (rMOMP) of Chlamydia trachomatis, and may be a promising vaccine delivery system. Herein we evaluated the immune-potentiating potential of PLGA by encapsulating the full-length rMOMP (PLGA-rMOMP), characterizing it in vitro, and investigating its immunogenicity in vivo. Our hypothesis was that PLGA-rMOMP triggers Th1 immune responses in mice, which are desirable prerequisites for a C. trachomatis candidate nanovaccine. Physical-structural characterizations of PLGA-rMOMP revealed its size (approximately 272 nm), zeta potential (-14.30 mV), apparent spherical smooth morphology, and continuous slow release pattern. PLGA potentiated the ability of encapsulated rMOMP to trigger production of cytokines and chemokines by mouse J774 macrophages. Flow cytometric analyses revealed that spleen cells from BALB/c mice immunized with PLGA-rMOMP had elevated numbers of CD4+ and CD8+ T cell subsets, and secreted more rMOMP-specific interferon-gamma (Th1) and interleukin (IL)-12p40 (Th1/Th17) than IL-4 and IL-10 (Th2) cytokines. PLGA-rMOMP-immunized mice produced higher serum immunoglobulin (Ig)G and IgG2a (Th1) than IgG1 (Th2) rMOMP-specific antibodies. Notably, sera from PLGA-rMOMP-immunized mice had a 64-fold higher Th1 than Th2 antibody titer, whereas mice immunized with rMOMP in Freund's adjuvant had only a four-fold higher Th1 than Th2 antibody titer, suggesting primarily induction of a Th1 antibody response in PLGA-rMOMP-immunized mice. Our data underscore PLGA as an effective delivery system for a C. trachomatis vaccine. The capacity of PLGA-rMOMP to trigger primarily Th1 immune responses in mice promotes it as a highly desirable candidate nanovaccine against C. trachomatis.

The Bacterium Frischella perrara Causes Scab Formation in the Gut of its Honeybee Host

PubMed Central

Bartlett, Kelsey D.; Moran, Nancy A.

2015-01-01

ABSTRACT Honeybees harbor well-defined bacterial communities in their guts. The major members of these communities appear to benefit the host, but little is known about how they interact with the host and specifically how they interface with the host immune system. In the pylorus, a short region between the midgut and hindgut, honeybees frequently exhibit scab-like structures on the epithelial gut surface. These structures are reminiscent of a melanization response of the insect immune system. Despite the wide distribution of this phenotype in honeybee populations, its cause has remained elusive. Here, we show that the presence of a common member of the bee gut microbiota, the gammaproteobacterium Frischella perrara, correlates with the appearance of the scab phenotype. Bacterial colonization precedes scab formation, and F. perrara specifically localizes to the melanized regions of the host epithelium. Under controlled laboratory conditions, we demonstrate that exposure of microbiota-free bees to F. perrara but not to other bacteria results in scab formation. This shows that F. perrara can become established in a spatially restricted niche in the gut and triggers a morphological change of the epithelial surface, potentially due to a host immune response. As an intermittent colonizer, this bacterium holds promise for addressing questions of community invasion in a simple yet relevant model system. Moreover, our results show that gut symbionts of bees engage in differential host interactions that are likely to affect gut homeostasis. Future studies should focus on how these different gut bacteria impact honeybee health. PMID:25991680

Bacteria-Triggered Systemic Immunity in Barley Is Associated with WRKY and ETHYLENE RESPONSIVE FACTORs But Not with Salicylic Acid1[C][W

PubMed Central

Dey, Sanjukta; Wenig, Marion; Langen, Gregor; Sharma, Sapna; Kugler, Karl G.; Knappe, Claudia; Hause, Bettina; Bichlmeier, Marlies; Babaeizad, Valiollah; Imani, Jafargholi; Janzik, Ingar; Stempfl, Thomas; Hückelhoven, Ralph; Kogel, Karl-Heinz; Mayer, Klaus F.X.

2014-01-01

Leaf-to-leaf systemic immune signaling known as systemic acquired resistance is poorly understood in monocotyledonous plants. Here, we characterize systemic immunity in barley (Hordeum vulgare) triggered after primary leaf infection with either Pseudomonas syringae pathovar japonica (Psj) or Xanthomonas translucens pathovar cerealis (Xtc). Both pathogens induced resistance in systemic, uninfected leaves against a subsequent challenge infection with Xtc. In contrast to systemic acquired resistance in Arabidopsis (Arabidopsis thaliana), systemic immunity in barley was not associated with NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 or the local or systemic accumulation of salicylic acid. Instead, we documented a moderate local but not systemic induction of abscisic acid after infection of leaves with Psj. In contrast to salicylic acid or its functional analog benzothiadiazole, local applications of the jasmonic acid methyl ester or abscisic acid triggered systemic immunity to Xtc. RNA sequencing analysis of local and systemic transcript accumulation revealed unique gene expression changes in response to both Psj and Xtc and a clear separation of local from systemic responses. The systemic response appeared relatively modest, and quantitative reverse transcription-polymerase chain reaction associated systemic immunity with the local and systemic induction of two WRKY and two ETHYLENE RESPONSIVE FACTOR (ERF)-like transcription factors. Systemic immunity against Xtc was further associated with transcriptional changes after a secondary/systemic Xtc challenge infection; these changes were dependent on the primary treatment. Taken together, bacteria-induced systemic immunity in barley may be mediated in part by WRKY and ERF-like transcription factors, possibly facilitating transcriptional reprogramming to potentiate immunity. PMID:25332505

Regulatory dendritic cells: there is more than just immune activation.

PubMed

Schmidt, Susanne V; Nino-Castro, Andrea C; Schultze, Joachim L

2012-01-01

The immune system exists in a delicate equilibrium between inflammatory responses and tolerance. This unique feature allows the immune system to recognize and respond to potential threats in a controlled but normally limited fashion thereby preventing a destructive overreaction against healthy tissues. While the adaptive immune system was the major research focus concerning activation vs. tolerance in the immune system more recent findings suggest that cells of the innate immune system are important players in the decision between effective immunity and induction of tolerance or immune inhibition. Among immune cells of the innate immune system dendritic cells (DCs) have a special function linking innate immune functions with the induction of adaptive immunity. DCs are the primary professional antigen presenting cells (APCs) initiating adaptive immune responses. They belong to the hematopoietic system and arise from CD34(+) stem cells in the bone marrow. Particularly in the murine system two major subgroups of DCs, namely myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) can be distinguished. DCs are important mediators of innate and adaptive immunity mostly due to their remarkable capacity to present processed antigens via major histocompatibility complexes (MHC) to T cells and B cells in secondary lymphoid organs. A large body of literature has been accumulated during the last two decades describing which role DCs play during activation of T cell responses but also during the establishment and maintenance of central tolerance (Steinman et al., 2003). While the concept of peripheral tolerance has been clearly established during the last years, the role of different sets of DCs and their particular molecular mechanisms of immune deviation has not yet fully been appreciated. In this review we summarize accumulating evidence about the role of regulatory DCs in situations where the balance between tolerance and immunogenicity has been altered leading to pathologic conditions such as chronic inflammation or malignancies.

Regulatory dendritic cells: there is more than just immune activation

PubMed Central

Schmidt, Susanne V.; Nino-Castro, Andrea C.; Schultze, Joachim L.

2012-01-01

The immune system exists in a delicate equilibrium between inflammatory responses and tolerance. This unique feature allows the immune system to recognize and respond to potential threats in a controlled but normally limited fashion thereby preventing a destructive overreaction against healthy tissues. While the adaptive immune system was the major research focus concerning activation vs. tolerance in the immune system more recent findings suggest that cells of the innate immune system are important players in the decision between effective immunity and induction of tolerance or immune inhibition. Among immune cells of the innate immune system dendritic cells (DCs) have a special function linking innate immune functions with the induction of adaptive immunity. DCs are the primary professional antigen presenting cells (APCs) initiating adaptive immune responses. They belong to the hematopoietic system and arise from CD34+ stem cells in the bone marrow. Particularly in the murine system two major subgroups of DCs, namely myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) can be distinguished. DCs are important mediators of innate and adaptive immunity mostly due to their remarkable capacity to present processed antigens via major histocompatibility complexes (MHC) to T cells and B cells in secondary lymphoid organs. A large body of literature has been accumulated during the last two decades describing which role DCs play during activation of T cell responses but also during the establishment and maintenance of central tolerance (Steinman et al., 2003). While the concept of peripheral tolerance has been clearly established during the last years, the role of different sets of DCs and their particular molecular mechanisms of immune deviation has not yet fully been appreciated. In this review we summarize accumulating evidence about the role of regulatory DCs in situations where the balance between tolerance and immunogenicity has been altered leading to pathologic conditions such as chronic inflammation or malignancies. PMID:22969767

Impact of aging immune system on neurodegeneration and potential immunotherapies.

PubMed

Liang, Zhanfeng; Zhao, Yang; Ruan, Linhui; Zhu, Linnan; Jin, Kunlin; Zhuge, Qichuan; Su, Dong-Ming; Zhao, Yong

2017-10-01

The interaction between the nervous and immune systems during aging is an area of avid interest, but many aspects remain unclear. This is due, not only to the complexity of the aging process, but also to a mutual dependency and reciprocal causation of alterations and diseases between both the nervous and immune systems. Aging of the brain drives whole body systemic aging, including aging-related changes of the immune system. In turn, the immune system aging, particularly immunosenescence and T cell aging initiated by thymic involution that are sources of chronic inflammation in the elderly (termed inflammaging), potentially induces brain aging and memory loss in a reciprocal manner. Therefore, immunotherapeutics including modulation of inflammation, vaccination, cellular immune therapies and "protective autoimmunity" provide promising approaches to rejuvenate neuroinflammatory disorders and repair brain injury. In this review, we summarize recent discoveries linking the aging immune system with the development of neurodegeneration. Additionally, we discuss potential rejuvenation strategies, focusing aimed at targeting the aging immune system in an effort to prevent acute brain injury and chronic neurodegeneration during aging. Copyright © 2017 Elsevier Ltd. All rights reserved.

Robustness trade-offs and host–microbial symbiosis in the immune system

PubMed Central

Kitano, Hiroaki; Oda, Kanae

2006-01-01

The immune system provides organisms with robustness against pathogen threats, yet it also often adversely affects the organism as in autoimmune diseases. Recently, the molecular interactions involved in the immune system have been uncovered. At the same time, the role of the bacterial flora and its interactions with the host immune system have been identified. In this article, we try to reconcile these findings to draw a consistent picture of the host defense system. Specifically, we first argue that the network of molecular interactions involved in immune functions has a bow-tie architecture that entails inherent trade-offs among robustness, fragility, resource limitation, and performance. Second, we discuss the possibility that commensal bacteria and the host immune system constitute an integrated defense system. This symbiotic association has evolved to optimize its robustness against pathogen attacks and nutrient perturbations by harboring a broad range of microorganisms. Owing to the inherent propensity of a host immune system toward hyperactivity, maintenance of bacterial flora homeostasis might be particularly important in the development of preventive strategies against immune disorders such as autoimmune diseases. PMID:16738567

Technological and Organizational Context around Immunization Reporting and Interoperability in Minnesota

PubMed Central

Rajamani, Sripriya; Roche, Erin; Soderberg, Karen; Bieringer, Aaron

2014-01-01

Background: Immunization information systems (IIS) operate in an evolving health care landscape with technology changes driven by initiatives such as the Centers for Medicare and Medicaid Services EHR incentive program, promoting adoption and use of electronic health record (EHR) systems, including standards-based public health reporting. There is flux in organizational affiliations to support models such as accountable care organizations (ACO). These impact institutional structure of how reporting of immunizations occurs and the methods adopted. Objectives: To evaluate the technical and organizational characteristics of healthcare provider reporting of immunizations to public health in Minnesota and to assess the adoption of standardized codes, formats and transport. Methods: Data on organizations and reporting status was obtained from Minnesota IIS (Minnesota Immunization Information Connection: MIIC) by collating information from existing lists, specialized queries and review of annual reports. EHR adoption data of clinics was obtained in collaboration with informatics office supporting the Minnesota e-Health Initiative. These data from various sources were merged, checked for quality to create a current state assessment of immunization reporting and results validated with subject matter experts. Results: Standards-based reporting of immunizations to MIIC increased to 708 sites over the last 3 years. A growth in automated real-time reporting occurred in 2013 with 143 new sites adopting the method. Though the uptake of message standards (HL7) has increased, the adoption of current version of HL7 and web services transport remains low. The EHR landscape is dominated by a single vendor (used by 40% of clinics) in the state. There is trend towards centralized reporting of immunizations with an organizational unit reporting for many sites ranging from 4 to 140 sites. Conclusion: High EHR adoption in Minnesota, predominance of a vendor in the market, and centralized reporting models present opportunities for better interoperability and also adaptation of strategies to fit this landscape. It is essential for IIS managers to have a good understanding of their constituent landscape for technical assistance and program planning purposes. PMID:25598866

[Mechanisms of immune deposit formation in glomerulonephritis].

PubMed

Bussolati, B; Camussi, G

1996-03-01

Recent experimental studies allowed the identification of several mechanisms of immune deposit formation, which are able to reproduce the morphological and clinical pattern of human glomerulonephritis. Moreover, it was shown that most of the lesions considered, in the past, as due to circulating immune complexes (IC), are instead caused by the "in situ" formation of IC. As a result of these studies, the following schematic classification was proposed: 1) immune deposits formed by glomerular localization of IC primarily formed in the circulation; 2) immune deposits formed "in situ" by reaction of circulating antibodies with fixed structural antigens; 3) immune deposits formed "in situ" by antibodies reactive with movable structural antigens; 4) immune deposits formed "in situ" by antibodies reactive with sequestered antigens leaking out of tissues; 5) IC formed "in situ" by antibodies reactive with exogenous or non-glomerular endogenous antigens planted in the glomeruli; 6) ANCA-associated glomerular disease.

Invited essay: Cognitive influences on the psychological immune system.

PubMed

Rachman, S J

2016-12-01

The construct of the psychological immune system is described and analysed. The direct and indirect cognitive influences on the system are discussed, and the implications of adding a cognitive construal to the influential model of a behavioural immune system are considered. The psychological immune system has two main properties: defensive and healing. It encompasses a good amount of health-related phenomena that is outside the scope of the behavioural model or the biological immune system. Evidence pertaining to the psychological immune system includes meta-analyses of the associations between psychological variables such as positive affect/wellbeing and diseases and mortality, and associations between wellbeing and positive health. The results of long-term prospective studies are consistent with the conclusions drawn from the meta-analyses. Laboratory investigations of the effects of psychological variables on the biological immune system show that negative affect can slow wound-healing, and positive affect can enhance resistance to infections, for example in experiments involving the introduction of the rhinovirus and the influenza A virus. A number of problems concerning the assessment of the functioning of the psychological immune system are considered, and the need to develop techniques for determining when the system is active or not, is emphasized. This problem is particularly challenging when trying to assess the effects of the psychological immune system during a prolonged psychological intervention, such as a course of resilience training. Copyright © 2016 Elsevier Ltd. All rights reserved.

Local and systemic tumor immune dynamics

NASA Astrophysics Data System (ADS)

Enderling, Heiko

Tumor-associated antigens, stress proteins, and danger-associated molecular patterns are endogenous immune adjuvants that can both initiate and continually stimulate an immune response against a tumor. In retaliation, tumors can hijack intrinsic immune regulatory programs that are intended to prevent autoimmune disease, thereby facilitating continued growth despite the activated antitumor immune response. In metastatic disease, this ongoing tumor-immune battle occurs at each site. Adding an additional layer of complexity, T cells activated at one tumor site can cycle through the blood circulation system and extravasate in a different anatomic location to surveil a distant metastasis. We propose a mathematical modeling framework that incorporates the trafficking of activated T cells between metastatic sites. We extend an ordinary differential equation model of tumor-immune system interactions to multiple metastatic sites. Immune cells are activated in response to tumor burden and tumor cell death, and are recruited from tumor sites elsewhere in the body. A model of T cell trafficking throughout the circulatory system can inform the tumor-immune interaction model about the systemic distribution and arrival of T cells at specific tumor sites. Model simulations suggest that metastases not only contribute to immune surveillance, but also that this contribution varies between metastatic sites. Such information may ultimately help harness the synergy of focal therapy with the immune system to control metastatic disease.

The Cost of Doing Business: Cost Structure of Electronic Immunization Registries

PubMed Central

Fontanesi, John M; Flesher, Don S; De Guire, Michelle; Lieberthal, Allan; Holcomb, Kathy

2002-01-01

Objective To predict the true cost of developing and maintaining an electronic immunization registry, and to set the framework for developing future cost-effective and cost-benefit analysis. Data Sources/Study Setting Primary data collected at three immunization registries located in California, accounting for 90 percent of all immunization records in registries in the state during the study period. Study Design A parametric cost analysis compared registry development and maintenance expenditures to registry performance requirements. Data Collection/Extraction Methods Data were collected at each registry through interviews, reviews of expenditure records, technical accomplishments development schedules, and immunization coverage rates. Principal Findings The cost of building immunization registries is predictable and independent of the hardware/software combination employed. The effort requires four man-years of technical effort or approximately $250,000 in 1998 dollars. Costs for maintaining a registry were approximately $5,100 per end user per three-year period. Conclusions There is a predictable cost structure for both developing and maintaining immunization registries. The cost structure can be used as a framework for examining the cost-effectiveness and cost-benefits of registries. The greatest factor effecting improvement in coverage rates was ongoing, user-based administrative investment. PMID:12479497

Novel Target for Ameliorating Pain and Other Problems after SCI: Spontaneous Activity in Nociceptors

DTIC Science & Technology

2016-06-01

BSCB will permit blood-borne mye- loid and lymphoid immune cells to enter the spinal cord parenchyma and exert direct inflammatory actions on central...primitive innate immune system is the first line of defense against pathogens and toxins; it is always present and it depends upon diverse cell types that...adaptive immune system, the innate immune system does not em- ploy antigen-specific humoral and cell -mediated immunity mecha- nisms. Two innate immune

Crosstalk between bone niche and immune system: osteoimmunology signaling as a potential target for cancer treatment.

PubMed

Criscitiello, Carmen; Viale, Giulia; Gelao, Lucia; Esposito, Angela; De Laurentiis, Michele; De Placido, Sabino; Santangelo, Michele; Goldhirsch, Aron; Curigliano, Giuseppe

2015-02-01

There is a well recognized link between the bone and the immune system and in recent years there has been a major effort to elucidate the multiple functions of the molecules expressed in both bone and immune cells. Several molecules that were initially identified and studied in the immune system have been shown to have essential functions also in the bone. An interdisciplinary field embracing immune and bone biology has been brought together and called "osteoimmunology". The co-regulation of the skeletal and immune systems strikingly exemplifies the extreme complexity of such an interaction. Their interdependency must be considered in designing therapeutic approaches for either of the two systems. In other words, it is necessary to think of the osteoimmune system as a complex physiological unit. Denosumab was originally introduced to specifically target bone resorption, but it is now under evaluation for its effect on the long term immune response. Similarly, our current and still growing knowledge of the intimate link between the immune system and bone will be beneficial for the safety of drugs targeting either of these integrated systems. Given the large number of molecules exerting functions on both the skeletal and immune systems, osteoimmunological understanding is becoming increasingly important. Both bone and immune systems are frequently disrupted in cancer; and they may be crucial in regulating tumor growth and progression. Some therapies - such as bisphosphonates and receptor activator of NF-κB ligand (RANKL) targeted drugs - that aim at reducing pathologic osteolysis in cancer may interact with the immune system, thus providing potential favorable effects on survival. Copyright © 2014 Elsevier Ltd. All rights reserved.

Neuroimmune Basis of Methamphetamine Toxicity

PubMed Central

Loftis, Jennifer M.; Janowsky, Aaron

2015-01-01

Although it is not known which antigen-specific immune responses (or if antigen-specific immune responses) are relevant or required for methamphetamine's neurotoxic effects, it is apparent that methamphetamine exposure is associated with significant effects on adaptive and innate immunity. Alterations in lymphocyte activity and number, changes in cytokine signaling, impairments in phagocytic functions, and glial activation and gliosis have all been reported. These drug-induced changes in immune response, particularly within the CNS, are now thought to play a critical role in the addiction process for methamphetamine dependence as well as for other substance use disorders. In Section 2, methamphetamine's effects on glial cell (e.g., microglia and astrocytes) activity and inflammatory signaling cascades are summarized, including how alterations in immune cell function can induce the neurotoxic and addictive effects of methamphetamine. Section 2 also describes neurotransmitter involvement in the modulation of methamphetamine's inflammatory effects. Section 3 discusses the very recent use of pharmacological and genetic animal models which have helped elucidate the behavioral effects of methamphetamine's neurotoxic effects and the role of the immune system. Section 4 is focused on the effects of methamphetamine on blood–brain barrier integrity and associated immune consequences. Clinical considerations such as the combined effects of methamphetamine and HIV and/or HCV on brain structure and function are included in Section 4. Finally, in Section 5, immune-based treatment strategies are reviewed, with a focus on vaccine development, neuroimmune therapies, and other anti-inflammatory approaches. PMID:25175865

Plant innate immunity: an updated insight into defense mechanism.

PubMed

Muthamilarasan, Mehanathan; Prasad, Manoj

2013-06-01

Plants are invaded by an array of pathogens of which only a few succeed in causing disease. The attack by others is countered by a sophisticated immune system possessed by the plants. The plant immune system is broadly divided into two, viz. microbial-associated molecular-patterns-triggered immunity (MTI) and effector-triggered immunity (ETI). MTI confers basal resistance, while ETI confers durable resistance, often resulting in hypersensitive response. Plants also possess systemic acquired resistance (SAR), which provides long-term defense against a broad-spectrum of pathogens. Salicylic-acid-mediated systemic acquired immunity provokes the defense response throughout the plant system during pathogen infection at a particular site. Trans-generational immune priming allows the plant to heritably shield their progeny towards pathogens previously encountered. Plants circumvent the viral infection through RNA interference phenomena by utilizing small RNAs. This review summarizes the molecular mechanisms of plant immune system, and the latest breakthroughs reported in plant defense. We discuss the plant–pathogen interactions and integrated defense responses in the context of presenting an integral understanding in plant molecular immunity.

Peptide Modulation of Class I Major Histocompatibility Complex Protein Molecular Flexibility and the Implications for Immune Recognition*

PubMed Central

Hawse, William F.; Gloor, Brian E.; Ayres, Cory M.; Kho, Kevin; Nuter, Elizabeth; Baker, Brian M.

2013-01-01

T cells use the αβ T cell receptor (TCR) to recognize antigenic peptides presented by class I major histocompatibility complex proteins (pMHCs) on the surfaces of antigen-presenting cells. Flexibility in both TCRs and peptides plays an important role in antigen recognition and discrimination. Less clear is the role of flexibility in the MHC protein; although recent observations have indicated that mobility in the MHC can impact TCR recognition in a peptide-dependent fashion, the extent of this behavior is unknown. Here, using hydrogen/deuterium exchange, fluorescence anisotropy, and structural analyses, we show that the flexibility of the peptide binding groove of the class I MHC protein HLA-A*0201 varies significantly with different peptides. The variations extend throughout the binding groove, impacting regions contacted by TCRs as well as other activating and inhibitory receptors of the immune system. Our results are consistent with statistical mechanical models of protein structure and dynamics, in which the binding of different peptides alters the populations and exchange kinetics of substates in the MHC conformational ensemble. Altered MHC flexibility will influence receptor engagement, impacting conformational adaptations, entropic penalties associated with receptor recognition, and the populations of binding-competent states. Our results highlight a previously unrecognized aspect of the “altered self” mechanism of immune recognition and have implications for specificity, cross-reactivity, and antigenicity in cellular immunity. PMID:23836912

Probiotics, antibiotics and the immune responses to vaccines.

PubMed

Praharaj, Ira; John, Sushil M; Bandyopadhyay, Rini; Kang, Gagandeep

2015-06-19

Orally delivered vaccines have been shown to perform poorly in developing countries. There are marked differences in the structure and the luminal environment of the gut in developing countries resulting in changes in immune and barrier function. Recent studies using newly developed technology and analytic methods have made it increasingly clear that the intestinal microbiota activate a multitude of pathways that control innate and adaptive immunity in the gut. Several hypotheses have been proposed for the underperformance of oral vaccines in developing countries, and modulation of the intestinal microbiota is now being tested in human clinical trials. Supplementation with specific strains of probiotics has been shown to have modulatory effects on intestinal and systemic immune responses in animal models and forms the basis for human studies with vaccines. However, most studies published so far that have evaluated the immune response to vaccines in children and adults have been small and results have varied by age, antigen, type of antibody response and probiotic strain. Use of anthelminthic drugs in children has been shown to possibly increase immunogenicity following oral cholera vaccination, lending further support to the rationale for modulation of the immune response to oral vaccination through the intestinal microbiome. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Clay Nanoparticles Elicit Long-Term Immune Responses by Forming Biodegradable Depots for Sustained Antigen Stimulation.

PubMed

Chen, Weiyu; Zuo, Huali; Li, Bei; Duan, Chengcheng; Rolfe, Barbara; Zhang, Bing; Mahony, Timothy J; Xu, Zhi Ping

2018-05-01

Nanomaterials have been widely tested as new generation vaccine adjuvants, but few evoke efficient immunoreactions. Clay nanoparticles, for example, layered double hydroxide (LDH) and hectorite (HEC) nanoparticles, have shown their potent adjuvanticity in generating effective and durable immune responses. However, the mechanism by which clay nanoadjuvants stimulate the immune system is not well understood. Here, it is demonstrated that LDH and HEC-antigen complexes form loose agglomerates in culture medium/serum. They also form nodules with loose structures in tissue after subcutaneous injection, where they act as a depot for up to 35 d. More importantly, clay nanoparticles actively and continuously recruit immune cells into the depot for up to one month, and stimulate stronger immune responses than FDA-approved adjuvants, Alum and QuilA. Sustained antigen release is also observed in clay nanoparticle depots, with 50-60% antigen released after 35 d. In contrast, Alum-antigen complexes show minimal antigen release from the depot. Importantly, LDH and HEC are more effective than QuilA and Alum in promoting memory T-cell proliferation. These findings suggest that both clay nanoadjuvants can serve as active vaccine platforms for sustained and potent immune responses. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of ionizing radiation on the immune system with special emphasis on the interaction of dendritic and T cells.

PubMed

Manda, Katrin; Glasow, Annegret; Paape, Daniel; Hildebrandt, Guido

2012-01-01

Dendritic cells (DCs), as professional antigen-presenting cells, are members of the innate immune system and function as key players during the induction phase of adaptive immune responses. Uptake, processing, and presentation of antigens direct the outcome toward either tolerance or immunity. The cells of the immune system are among the most highly radiosensitive cells in the body. For high doses of ionizing radiation (HD-IR) both immune-suppressive effects after whole body irradiation and possible immune activation during tumor therapy were observed. On the other hand, the effects of low doses of ionizing radiation (LD-IR) on the immune system are controversial and seem to show high variability among different individuals and species. There are reports revealing that protracted LD-IR can result in radioresistance. But immune-suppressive effects of chronic LD-IR are also reported, including the killing or sensitizing of certain cell types. This article shall review the current knowledge of radiation-induced effects on the immune system, paying special attention to the interaction of DCs and T cells.

Measuring the immune system: a comprehensive approach for the analysis of immune functions in humans.

PubMed

Claus, Maren; Dychus, Nicole; Ebel, Melanie; Damaschke, Jürgen; Maydych, Viktoriya; Wolf, Oliver T; Kleinsorge, Thomas; Watzl, Carsten

2016-10-01

The immune system is essential to provide protection from infections and cancer. Disturbances in immune function can therefore directly affect the health of the affected individual. Many extrinsic and intrinsic factors such as exposure to chemicals, stress, nutrition and age have been reported to influence the immune system. These influences can affect various components of the immune system, and we are just beginning to understand the causalities of these changes. To investigate such disturbances, it is therefore essential to analyze the different components of the immune system in a comprehensive fashion. Here, we demonstrate such an approach which provides information about total number of leukocytes, detailed quantitative and qualitative changes in the composition of lymphocyte subsets, cytokine levels in serum and functional properties of T cells, NK cells and monocytes. Using samples from a cohort of 24 healthy volunteers, we demonstrate the feasibility of our approach to detect changes in immune functions.

Behavioural conditioning of immune functions: how the central nervous system controls peripheral immune responses by evoking associative learning processes.

PubMed

Riether, Carsten; Doenlen, Raphaël; Pacheco-López, Gustavo; Niemi, Maj-Britt; Engler, Andrea; Engler, Harald; Schedlowski, Manfred

2008-01-01

During the last 30 years of psychoneuroimmunology research the intense bi-directional communication between the central nervous system (CNS) and the immune system has been demonstrated in studies on the interaction between the nervous-endocrine-immune systems. One of the most intriguing examples of such interaction is the capability of the CNS to associate an immune status with specific environmental stimuli. In this review, we systematically summarize experimental evidence demonstrating the behavioural conditioning of peripheral immune functions. In particular, we focus on the mechanisms underlying the behavioural conditioning process and provide a theoretical framework that indicates the potential feasibility of behaviourally conditioned immune changes in clinical situations.

Virology, Immunology, and Clinical Course of HIV Infection.

ERIC Educational Resources Information Center

McCutchan, J. Allen

1990-01-01

Presents overview of medical aspects of human immunodeficiency virus Type 1 (HIV-1) disease. Addresses structure and replication of virus, current methods for detecting HIV-1 in infected persons, effects of the virus on immune system, and clinical course of HIV-1 disease. Emphasizes variable causes of progression through HIV-1 infection stages;…

Focused Ultrasound Immunotherapy for Central Nervous System Pathologies: Challenges and Opportunities

PubMed Central

Curley, Colleen T.; Sheybani, Natasha D.; Bullock, Timothy N.; Price, Richard J.

2017-01-01

Immunotherapy is rapidly emerging as the cornerstone for the treatment of several forms of metastatic cancer, as well as for a host of other pathologies. Meanwhile, several new high-profile studies have uncovered remarkable linkages between the central nervous and immune systems. With these recent developments, harnessing the immune system for the treatment of brain pathologies is a promising strategy. Here, we contend that MR image-guided focused ultrasound (FUS) represents a noninvasive approach that will allow for favorable therapeutic immunomodulation in the setting of the central nervous system. One obstacle to effective immunotherapeutic drug delivery to the brain is the blood brain barrier (BBB), which refers to the specialized structure of brain capillaries that prevents transport of most therapeutics from the blood into brain tissue. When applied in the presence of circulating microbubbles, FUS can safely and transiently open the BBB to facilitate the delivery of immunotherapeutic agents into the brain parenchyma. Furthermore, it has been demonstrated that physical perturbations of the tissue microenvironment via FUS can modulate immune response in both normal and diseased tissue. In this review article, we provide an overview of FUS energy regimens and corresponding tissue bioeffects, followed by a review of the literature pertaining to FUS for therapeutic antibody delivery in normal brain and preclinical models of brain disease. We provide an overview of studies that demonstrate FUS-mediated immune modulation in both the brain and peripheral settings. Finally, we provide remarks on challenges facing FUS immunotherapy and opportunities for future expansion in this area. PMID:29109764

Food-Nonfood Discrimination in Ancestral Vertebrates: Gamete Cannibalism and the Origin of the Adaptive Immune System.

PubMed

Corcos, D

2015-11-01

Adaptive immunity is a complex system that appeared twice in vertebrates (in gnathostomes and in jawless fish) although it is not required for invertebrate defence. The adaptive immune system is tightly associated with self-non-self discrimination, and it is now clear that this interplay is not limited to the prevention of autoreactivity. Micro-organisms are usually considered for their pathogenicity or symbiotic ability, but, for most small metazoans, they mainly constitute food. Vertebrates are characterized by feeding by predation on larger preys, when compared to their ancestors who were filter feeders and ate micro-organisms. Predation gives a strong selective advantage, not only due to the availability of new food resources but also by the ability to eliminate competitors for environmental resources (intraguild predation (IGP)). Unlike size-structured IGP, intraspecific predation of juveniles, zygotes or gametes can be detrimental for species fitness in some circumstances. The ability of individuals to recognize highly polymorphic molecules on the surface of gametes present in the plankton and so distinguish self versus non-self gametes might have constituted a strong selective advantage in intraspecific competition. Here, I propose the theory that the capacity to rearrange receptors has been selected in ancestral vertebrates as a consequence of this strong need for discriminating between hetero-cannibalism versus filial cannibalism. This evolutionary origin sheds light on presently unexplained features of the immune system, including the existence of regulatory T cells and of non-pathogenic natural autoimmunity. © 2015 The Foundation for the Scandinavian Journal of Immunology.

The stress response and immune system share, borrow, and reconfigure their physiological network elements: Evidence from the insects.

PubMed

Adamo, Shelley A

2017-02-01

The classic biomedical view is that stress hormone effects on the immune system are largely pathological, especially if the stress is chronic. However, more recent interpretations have focused on the potential adaptive function of these effects. This paper examines stress response-immune system interactions from a physiological network perspective, using insects because of their simpler physiology. For example, stress hormones can reduce disease resistance, yet activating an immune response results in the release of stress hormones in both vertebrates and invertebrates. From a network perspective, this phenomenon is consistent with the 'sharing' of the energy-releasing ability of stress hormones by both the stress response and the immune system. Stress-induced immunosuppression is consistent with the stress response 'borrowing' molecular components from the immune system to increase the capacity of stress-relevant physiological processes (i.e. a trade off). The insect stress hormones octopamine and adipokinetic hormone can also 'reconfigure' the immune system to help compensate for the loss of some of the immune system's molecular resources (e.g. apolipophorin III). This view helps explain seemingly maladaptive interactions between the stress response and immune system. The adaptiveness of stress hormone effects on individual immune components may be apparent only from the perspective of the whole organism. These broad principles will apply to both vertebrates and invertebrates. Copyright © 2016 Elsevier Inc. All rights reserved.

Vitamin E, immunity, and infection

USDA-ARS?s Scientific Manuscript database

A normally functioning immune system is critical for the body to fight and eliminate invading pathogens from the environment. On the other hand, the immune system also protects the body from internal risks such as neoplasia growing within and autoimmune responses that attack self. The immune system ...

Chapter 2: Innate Immunity

PubMed Central

Turvey, Stuart E.; Broide, David H.

2009-01-01

Recent years have witnessed an explosion of interest in the innate immune system. Questions about how the innate immune system senses infection and empowers a protective immune response are being answered at the molecular level. These basic science discoveries are being translated into a more complete understanding of the central role innate immunity plays in the pathogenesis of many human infectious and inflammatory diseases. It is particularly exciting that we are already seeing a return on these scientific investments with the emergence of novel therapies to harness the power of the innate immune system. In this review we explore the defining characteristics of the innate immune system, and through more detailed examples, we highlight recent breakthroughs that have advanced our understanding of the role of innate immunity in human health and disease. PMID:19932920

Foetal immune programming: hormones, cytokines, microbes and regulatory T cells.

PubMed

Hsu, Peter; Nanan, Ralph

2014-10-01

In addition to genetic factors, environmental cues play important roles in shaping the immune system. The first environment that the developing foetal immune system encounters is the uterus. Although physically the mother and the foetus are separated by the placental membranes, various factors such as hormones and cytokines may provide "environmental cues" to the foetal immune system. Additionally, increasing evidence suggests that prenatal maternal environmental factors, particularly microbial exposure, might significantly influence the foetal immune system, affecting long-term outcomes, a concept termed foetal immune programming. Here we discuss the potential mediators of foetal immune programming, focusing on the role of pregnancy-related hormones, cytokines and regulatory T cells, which play a critical role in immune tolerance. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Phylogenetic aspects of the complement system.

PubMed

Zarkadis, I K; Mastellos, D; Lambris, J D

2001-01-01

During evolution two general systems of immunity have emerged: innate or, natural immunity and adaptive (acquired), or specific immunity. The innate system is phylogenetically older and is found in some form in all multicellular organisms, whereas the adaptive system appeared about 450 million years ago and is found in all vertebrates except jawless fish. The complement system in higher vertebrates plays an important role as an effector of both the innate and the acquired immune response, and also participates in various immunoregulatory processes. In lower vertebrates complement is activated by the alternative and lectin pathways and is primarily involved in the opsonization of foreign material. The Agnatha (the most primitive vertebrate species) possess the alternative and lectin pathways while cartilaginous fish are the first species in which the classical pathway appears following the emergence of immunoglobulins. The rest of the poikilothermic species, ranging from teleosts to reptilians, appear to contain a well-developed complement system resembling that of the homeothermic vertebrates. It seems that most of the complement components have appeared after the duplication of primordial genes encoding C3/C4/C5, fB/C2, C1s/C1r/MASP-1/MASP-2, and C6/C7/C8/C9 molecules, in a process that led to the formation of distinct activation pathways. However, unlike homeotherms, several species of poikilotherms (e.g. trout) have recently been shown to possess multiple forms of complement components (C3, factor B) that are structurally and functionally more diverse than those of higher vertebrates. We hypothesize that this remarkable diversity has allowed these animals to expand their innate capacity for immune recognition and response. Recent studies have also indicated the possible presence of complement receptors in protochordates and lower vertebrates. In conclusion, there is considerable evidence suggesting that the complement system is present in the entire lineage of deuterostomes, and regulatory complement components have been identified in all species beyond the protochordates, indicating that the mechanisms of complement activation and regulation have developed in parallel.

[Bone structure in rheumatoid arthritis].

PubMed

Ono, Kumiko; Ohashi, Satoru; Tanaka, Sakae; Matsumoto, Takuya

2013-07-01

In rheumatoid arthritis (RA) , the osteoclast pathway is activated by abnormal immune conditions accompanied by chronic inflammation, resulting in periarticular osteoporosis and local bone destruction around joints. In addition, multiple factors, including reduced physical activity and pharmacotherapies such as steroids, lead to systemic osteoporosis. These conditions cause decreasing bone mineral density and deterioration of bone quality, and expose patients to increased risk of fracture. Understanding the bone structures of RA and evaluating fracture risk are central to the treatment of RA.

Collective synchronization of self/non-self discrimination in T cell activation, across multiple spatio-temporal scales

NASA Astrophysics Data System (ADS)

Altan-Bonnet, Gregoire

The immune system is a collection of cells whose function is to eradicate pathogenic infections and malignant tumors while protecting healthy tissues. Recent work has delineated key molecular and cellular mechanisms associated with the ability to discriminate self from non-self agents. For example, structural studies have quantified the biophysical characteristics of antigenic molecules (those prone to trigger lymphocyte activation and a subsequent immune response). However, such molecular mechanisms were found to be highly unreliable at the individual cellular level. We will present recent efforts to build experimentally validated computational models of the immune responses at the collective cell level. Such models have become critical to delineate how higher-level integration through nonlinear amplification in signal transduction, dynamic feedback in lymphocyte differentiation and cell-to-cell communication allows the immune system to enforce reliable self/non-self discrimination at the organism level. In particular, we will present recent results demonstrating how T cells tune their antigen discrimination according to cytokine cues, and how competition for cytokine within polyclonal populations of cells shape the repertoire of responding clones. Additionally, we will present recent theoretical and experimental results demonstrating how competition between diffusion and consumption of cytokines determine the range of cell-cell communications within lymphoid organs. Finally, we will discuss how biochemically explicit models, combined with quantitative experimental validation, unravel the relevance of new feedbacks for immune regulations across multiple spatial and temporal scales.

"Kill" the messenger: Targeting of cell-derived microparticles in lupus nephritis.

PubMed

Nielsen, Christoffer T; Rasmussen, Niclas S; Heegaard, Niels H H; Jacobsen, Søren

2016-07-01

Immune complex (IC) deposition in the glomerular basement membrane (GBM) is a key early pathogenic event in lupus nephritis (LN). The clarification of the mechanisms behind IC deposition will enable targeted therapy in the future. Circulating cell-derived microparticles (MPs) have been proposed as major sources of extracellular autoantigens and ICs and triggers of autoimmunity in LN. The overabundance of galectin-3-binding protein (G3BP) along with immunoglobulins and a few other proteins specifically distinguish circulating MPs in patients with systemic lupus erythematosus (SLE), and this is most pronounced in patients with active LN. G3BP co-localizes with deposited ICs in renal biopsies from LN patients supporting a significant presence of MPs in the IC deposits. G3BP binds strongly to glomerular basement membrane proteins and integrins. Accordingly, MP surface proteins, especially G3BP, may be essential for the deposition of ICs in kidneys and thus for the ensuing formation of MP-derived electron dense structures in the GBM, and immune activation in LN. This review focuses on the notion of targeting surface molecules on MPs as an entirely novel treatment strategy in LN. By targeting MPs, a double hit may be achieved by attenuating both the autoantigenic fueling of immune complexes and the triggering of the adaptive immune system. Thereby, early pathogenic events may be blocked in contrast to current treatment strategies that primarily target and modulate later events in the cellular and humoral immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

Adaptive immune education by gut microbiota antigens.

PubMed

Zhao, Qing; Elson, Charles O

2018-05-01

Host-microbiota mutualism has been established during long-term co-evolution. A diverse and rich gut microbiota plays an essential role in the development and maturation of the host immune system. Education of the adaptive immune compartment by gut microbiota antigens is important in establishing immune balance. In particular, a critical time frame immediately after birth provides a 'window of opportunity' for the development of lymphoid structures, differentiation and maturation of T and B cells and, most importantly, establishment of immune tolerance to gut commensals. Depending on the colonization niche, antigen type and metabolic property of different gut microbes, CD4 T-cell responses vary greatly, which results in differentiation into distinct subsets. As a consequence, certain bacteria elicit effector-like immune responses by promoting the production of pro-inflammatory cytokines such as interferon-γ and interleukin-17A, whereas other bacteria favour the generation of regulatory CD4 T cells and provide help with gut homeostasis. The microbiota have profound effects on B cells also. Gut microbial exposure leads to a continuous diversification of B-cell repertoire and the production of T-dependent and -independent antibodies, especially IgA. These combined effects of the gut microbes provide an elegant educational process to the adaptive immune network. Contrariwise, failure of this process results in a reduced homeostasis with the gut microbiota, and an increased susceptibility to various immune disorders, both inside and outside the gut. With more definitive microbial-immune relations waiting to be discovered, modulation of the host gut microbiota has a promising future for disease intervention. © 2018 John Wiley & Sons Ltd.

Physical Theory of the Competition that Allows HIV to Escape from the Immune System

NASA Astrophysics Data System (ADS)

Wang, Guanyu; Deem, Michael W.

2006-11-01

Competition within the immune system may degrade immune control of viral infections. We formalize the evolution that occurs in both HIV-1 and the immune system quasispecies. Inclusion of competition in the immune system leads to a novel balance between the immune response and HIV-1, in which the eventual outcome is HIV-1 escape rather than control. The analytical model reproduces the three stages of HIV-1 infection. We propose a vaccine regimen that may be able to reduce competition between T cells, potentially eliminating the third stage of HIV-1.

Antigen discovery and delivery of subunit vaccines by nonliving bacterial ghost vectors.

PubMed

Walcher, Petra; Mayr, Ulrike B; Azimpour-Tabrizi, Chakameh; Eko, Francis O; Jechlinger, Wolfgang; Mayrhofer, Peter; Alefantis, Tim; Mujer, Cesar V; DelVecchio, Vito G; Lubitz, Werner

2004-12-01

The bacterial ghost (BG) platform system is a novel vaccine delivery system endowed with intrinsic adjuvant properties. BGs are nonliving Gram-negative bacterial cell envelopes which are devoid of their cytoplasmic contents, yet maintain their cellular morphology and antigenic structures, including bioadhesive properties. The main advantages of BGs as carriers of subunit vaccines include their ability to stimulate a high immune response and to target the carrier itself to primary antigen-presenting cells. The intrinsic adjuvant properties of BGs enhance the immune response to target antigens, including T-cell activation and mucosal immunity. Since native and foreign antigens can be carried in the envelope complex of BGs, combination vaccines with multiple antigens of diverse origin can be presented to the immune system simultaneously. Beside the capacity of BGs to function as carriers of protein antigens, they also have a high loading capacity for DNA. Thus, loading BGs with recombinant DNA takes advantage of the excellent bioavailability for DNA-based vaccines and the high expression rates of the DNA-encoded antigens in target cell types such as macrophages and dendritic cells. There are many spaces within BGs including the inner and outer membranes, the periplasmic space and the internal lumen which can carry antigens, DNA or mediators of the immune response. All can be used for subunit antigen to design new vaccine candidates with particle presentation technology. In addition, the fact that BGs can also carry piggyback large-size foreign antigen particles, increases the technologic usefulness of BGs as combination vaccines against viral and bacterial pathogens. Furthermore, the BG antigen carriers can be stored as freeze-dried preparations at room temperature for extended periods without loss of efficacy. The potency, safety and relatively low production cost of BGs offer a significant technical advantage over currently utilized vaccine technologies.

Murabutide revisited: a review of its pleiotropic biological effects.

PubMed

Jakopin, Žiga

2013-01-01

Despite the great efforts put into their development, the list of clinically approved immunological adjuvants is still very short. Evolution of the knowledge of the immune system has enabled for rational design of novel adjuvants and has led to the conclusion that more than one type of adjuvant will be required. Derivatives of muramyl dipeptide (MDP), the minimal immunomodulatory structure of bacterial cell wall peptidoglycan, have gained considerable attention in the past decades, because of their potent adjuvant effects. Murabutide is a safe derivative of MDP, which interacts with cells of the immune system, both innate and adaptive, and exerts its effect through activation of Nod2. The transcriptional response of murabutide-stimulated macrophages revealed enhanced expression of genes coding for various proteins such as immune mediators and their receptors, transcription factors and kinases, ion channels/transporters and proteins involved in cell metabolic activity, thus reflecting a broad spectrum of biological effects. In addition to its well recognized adjuvant effect, murabutide has also been shown to enhance the host's resistance against microbial infections, nonspecific resistance against tumors and the induction of cytokines and chemokines implicated in enhancing the immune response and hematopoesis. This article provides an insight into the mechanism of action of murabutide and its interactions with the cells of the immune system in vitro and in vivo. On account of its numerous biological effects, murabutide has been the subject of several clinical studies. Many of these have confirmed its potential to synergize with cytokines of therapeutic interest in potentiating the tumoricidal activity of macrophages or targeting chronic viral diseases, as well as reducing the cytokine dosage needed to achieve a therapeutic effect. This review covers the findings of all relevant studies and focuses on the role of murabutide and its potential in the treatment of several microbial diseases.

Evasion and Interactions of the Humoral Innate Immune Response in Pathogen Invasion, Autoimmune Disease, and Cancer

PubMed Central

Rettig, Trisha A.; Harbin, Julie N.; Harrington, Adelaide; Dohmen, Leonie; Fleming, Sherry D.

2015-01-01

The humoral innate immune system is composed of three major branches, complement, coagulation, and natural antibodies. To persist in the host, pathogens, such as bacteria, viruses, and cancers must evade parts of the innate humoral immune system. Disruptions in the humoral innate immune system also play a role in the development of autoimmune diseases. This review will examine how gram positive bacteria, viruses, cancer, and the autoimmune conditions Systemic Lupus Erythematosus and Anti-phospholipid syndrome, interact with these immune system components. Through examining evasion techniques it becomes clear that interplay between these three systems exists. By exploring the interplay and the evasion/disruption of the humoral innate immune system, we can develop a better understanding of pathogenic infections, cancer, and autoimmune disease development. PMID:26145788

Psychoneuroimmunology - psyche and autoimmunity.

PubMed

Ziemssen, Tjalf

2012-01-01

Psychoneuroimmunology is a relatively young field of research that investigates interactions between central nervous and immune system. The brain modulates the immune system by the endocrine and autonomic nervous system. Vice versa, the immune system modulates brain activity including sleep and body temperature. Based on a close functional and anatomical link, the immune and nervous systems act in a highly reciprocal manner. From fever to stress, the influence of one system on the other has evolved in an intricate manner to help sense danger and to mount an appropriate adaptive response. Over recent decades, reasonable evidence has emerged that these brain-to-immune interactions are highly modulated by psychological factors which influence immunity and autoimmune disease. For several diseases, the relevance of psychoneuroimmunological findings has already been demonstrated.

Modify the Histone to Win the Battle: Chromatin Dynamics in Plant–Pathogen Interactions

PubMed Central

Ramirez-Prado, Juan S.; Piquerez, Sophie J. M.; Bendahmane, Abdelhafid; Hirt, Heribert; Raynaud, Cécile; Benhamed, Moussa

2018-01-01

Relying on an immune system comes with a high energetic cost for plants. Defense responses in these organisms are therefore highly regulated and fine-tuned, permitting them to respond pertinently to the attack of a microbial pathogen. In recent years, the importance of the physical modification of chromatin, a highly organized structure composed of genomic DNA and its interacting proteins, has become evident in the research field of plant–pathogen interactions. Several processes, including DNA methylation, changes in histone density and variants, and various histone modifications, have been described as regulators of various developmental and defense responses. Herein, we review the state of the art in the epigenomic aspects of plant immunity, focusing on chromatin modifications, chromatin modifiers, and their physiological consequences. In addition, we explore the exciting field of understanding how plant pathogens have adapted to manipulate the plant epigenomic regulation in order to weaken their immune system and thrive in their host, as well as how histone modifications in eukaryotic pathogens are involved in the regulation of their virulence. PMID:29616066

Plant cell wall-mediated immunity: cell wall changes trigger disease resistance responses.

PubMed

Bacete, Laura; Mélida, Hugo; Miedes, Eva; Molina, Antonio

2018-02-01

Plants have evolved a repertoire of monitoring systems to sense plant morphogenesis and to face environmental changes and threats caused by different attackers. These systems integrate different signals into overreaching triggering pathways which coordinate developmental and defence-associated responses. The plant cell wall, a dynamic and complex structure surrounding every plant cell, has emerged recently as an essential component of plant monitoring systems, thus expanding its function as a passive defensive barrier. Plants have a dedicated mechanism for maintaining cell wall integrity (CWI) which comprises a diverse set of plasma membrane-resident sensors and pattern recognition receptors (PRRs). The PRRs perceive plant-derived ligands, such as peptides or wall glycans, known as damage-associated molecular patterns (DAMPs). These DAMPs function as 'danger' alert signals activating DAMP-triggered immunity (DTI), which shares signalling components and responses with the immune pathways triggered by non-self microbe-associated molecular patterns that mediate disease resistance. Alteration of CWI by impairment of the expression or activity of proteins involved in cell wall biosynthesis and/or remodelling, as occurs in some plant cell wall mutants, or by wall damage due to colonization by pathogens/pests, activates specific defensive and growth responses. Our current understanding of how these alterations of CWI are perceived by the wall monitoring systems is scarce and few plant sensors/PRRs and DAMPs have been characterized. The identification of these CWI sensors and PRR-DAMP pairs will help us to understand the immune functions of the wall monitoring system, and might allow the breeding of crop varieties and the design of agricultural strategies that would enhance crop disease resistance. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

The discontinuity theory of immunity

PubMed Central

Pradeu, Thomas; Vivier, Eric

2017-01-01

Some biological systems detect the rate of change in a stimulus rather than the stimulus itself only. We suggest that the immune system works in this way. According to the discontinuity theory of immunity, the immune system responds to sudden changes in antigenic stimulation and is rendered tolerant by slow or continuous stimulation. This basic principle, which is supported by recent data on immune checkpoints in viral infections, cancers, and allergies, can be seen as a unifying framework for diverse immune responses. PMID:28239677

Reciprocal Interactions of the Intestinal Microbiota and Immune System

PubMed Central

Maynard, Craig L.; Elson, Charles O.; Hatton, Robin D.; Weaver, Casey T.

2013-01-01

Preface Emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defense. These same attributes carry risk for immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how it integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks in order to treat and prevent disease. PMID:22972296

Psychological Stress and the Cutaneous Immune Response: Roles of the HPA Axis and the Sympathetic Nervous System in Atopic Dermatitis and Psoriasis

PubMed Central

Hall, Jessica M. F.; Cruser, desAnges; Podawiltz, Alan; Mummert, Diana I.; Jones, Harlan; Mummert, Mark E.

2012-01-01

Psychological stress, an evolutionary adaptation to the fight-or-flight response, triggers a number of physiological responses that can be deleterious under some circumstances. Stress signals activate the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Elements derived from those systems (e.g., cortisol, catecholamines and neuropeptides) can impact the immune system and possible disease states. Skin provides a first line of defense against many environmental insults. A number of investigations have indicated that the skin is especially sensitive to psychological stress, and experimental evidence shows that the cutaneous innate and adaptive immune systems are affected by stressors. For example, psychological stress has been shown to reduce recovery time of the stratum corneum barrier after its removal (innate immunity) and alters antigen presentation by epidermal Langerhans cells (adaptive immunity). Moreover, psychological stress may trigger or exacerbate immune mediated dermatological disorders. Understanding how the activity of the psyche-nervous -immune system axis impinges on skin diseases may facilitate coordinated treatment strategies between dermatologists and psychiatrists. Herein, we will review the roles of the HPA axis and the sympathetic nervous system on the cutaneous immune response. We will selectively highlight how the interplay between psychological stress and the immune system affects atopic dermatitis and psoriasis. PMID:22969795

Direct and Electronic Health Record Access to the Clinical Decision Support for Immunizations in the Minnesota Immunization Information System.

PubMed

Rajamani, Sripriya; Bieringer, Aaron; Wallerius, Stephanie; Jensen, Daniel; Winden, Tamara; Muscoplat, Miriam Halstead

2016-01-01

Immunization information systems (IIS) are population-based and confidential computerized systems maintained by public health agencies containing individual data on immunizations from participating health care providers. IIS hold comprehensive vaccination histories given across providers and over time. An important aspect to IIS is the clinical decision support for immunizations (CDSi), consisting of vaccine forecasting algorithms to determine needed immunizations. The study objective was to analyze the CDSi presentation by IIS in Minnesota (Minnesota Immunization Information Connection [MIIC]) through direct access by IIS interface and by access through electronic health records (EHRs) to outline similarities and differences. The immunization data presented were similar across the three systems examined, but with varying ability to integrate data across MIIC and EHR, which impacts immunization data reconciliation. Study findings will lead to better understanding of immunization data display, clinical decision support, and user functionalities with the ultimate goal of promoting IIS CDSi to improve vaccination rates.

Observation of the immune response of cells and tissue through multimodal label-free microscopy

NASA Astrophysics Data System (ADS)

Pavillon, Nicolas; Smith, Nicholas I.

2017-02-01

We present applications of a label-free approach to assess the immune response based on the combination of interferometric microscopy and Raman spectroscopy, which makes it possible to simultaneously acquire morphological and molecular information of live cells. We employ this approach to derive statistical models for predicting the activation state of macrophage cells based both on morphological parameters extracted from the high-throughput full-field quantitative phase imaging, and on the molecular content information acquired through Raman spectroscopy. We also employ a system for 3D imaging based on coherence gating, enabling specific targeting of the Raman channel to structures of interest within tissue.

Bacteria-triggered systemic immunity in barley is associated with WRKY and ETHYLENE RESPONSIVE FACTORs but not with salicylic acid.

PubMed

Dey, Sanjukta; Wenig, Marion; Langen, Gregor; Sharma, Sapna; Kugler, Karl G; Knappe, Claudia; Hause, Bettina; Bichlmeier, Marlies; Babaeizad, Valiollah; Imani, Jafargholi; Janzik, Ingar; Stempfl, Thomas; Hückelhoven, Ralph; Kogel, Karl-Heinz; Mayer, Klaus F X; Vlot, A Corina

2014-12-01

Leaf-to-leaf systemic immune signaling known as systemic acquired resistance is poorly understood in monocotyledonous plants. Here, we characterize systemic immunity in barley (Hordeum vulgare) triggered after primary leaf infection with either Pseudomonas syringae pathovar japonica (Psj) or Xanthomonas translucens pathovar cerealis (Xtc). Both pathogens induced resistance in systemic, uninfected leaves against a subsequent challenge infection with Xtc. In contrast to systemic acquired resistance in Arabidopsis (Arabidopsis thaliana), systemic immunity in barley was not associated with NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 or the local or systemic accumulation of salicylic acid. Instead, we documented a moderate local but not systemic induction of abscisic acid after infection of leaves with Psj. In contrast to salicylic acid or its functional analog benzothiadiazole, local applications of the jasmonic acid methyl ester or abscisic acid triggered systemic immunity to Xtc. RNA sequencing analysis of local and systemic transcript accumulation revealed unique gene expression changes in response to both Psj and Xtc and a clear separation of local from systemic responses. The systemic response appeared relatively modest, and quantitative reverse transcription-polymerase chain reaction associated systemic immunity with the local and systemic induction of two WRKY and two ETHYLENE RESPONSIVE FACTOR (ERF)-like transcription factors. Systemic immunity against Xtc was further associated with transcriptional changes after a secondary/systemic Xtc challenge infection; these changes were dependent on the primary treatment. Taken together, bacteria-induced systemic immunity in barley may be mediated in part by WRKY and ERF-like transcription factors, possibly facilitating transcriptional reprogramming to potentiate immunity. © 2014 American Society of Plant Biologists. All Rights Reserved.

Playing Hide and Seek: How Glycosylation of the Influenza Virus Hemagglutinin Can Modulate the Immune Response to Infection

PubMed Central

Tate, Michelle D.; Job, Emma R.; Deng, Yi-Mo; Gunalan, Vithiagaran; Maurer-Stroh, Sebastian; Reading, Patrick C.

2014-01-01

Seasonal influenza A viruses (IAV) originate from pandemic IAV and have undergone changes in antigenic structure, including addition of glycans to the hemagglutinin (HA) glycoprotein. The viral HA is the major target recognized by neutralizing antibodies and glycans have been proposed to shield antigenic sites on HA, thereby promoting virus survival in the face of widespread vaccination and/or infection. However, addition of glycans can also interfere with the receptor binding properties of HA and this must be compensated for by additional mutations, creating a fitness barrier to accumulation of glycosylation sites. In addition, glycans on HA are also recognized by phylogenetically ancient lectins of the innate immune system and the benefit provided by evasion of humoral immunity is balanced by attenuation of infection. Therefore, a fine balance must exist regarding the optimal pattern of HA glycosylation to offset competing pressures associated with recognition by innate defenses, evasion of humoral immunity and maintenance of virus fitness. In this review, we examine HA glycosylation patterns of IAV associated with pandemic and seasonal influenza and discuss recent advancements in our understanding of interactions between IAV glycans and components of innate and adaptive immunity. PMID:24638204

Immunotherapy: How the Immune System Fights Cancer

Cancer.gov

Immunotherapy uses the body’s immune system to fight cancer. This animation explains three types of immunotherapy used to treat cancer: nonspecific immune stimulation, T-cell transfer therapy, and immune checkpoint inhibitors.

Immunity in Drosophila melanogaster--from microbial recognition to whole-organism physiology.

PubMed

Buchon, Nicolas; Silverman, Neal; Cherry, Sara

2014-12-01

Since the discovery of antimicrobial peptide responses 40 years ago, the fruit fly Drosophila melanogaster has proven to be a powerful model for the study of innate immunity. Early work focused on innate immune mechanisms of microbial recognition and subsequent nuclear factor-κB signal transduction. More recently, D. melanogaster has been used to understand how the immune response is regulated and coordinated at the level of the whole organism. For example, researchers have used this model in studies investigating interactions between the microbiota and the immune system at barrier epithelial surfaces that ensure proper nutritional and immune homeostasis both locally and systemically. In addition, studies in D. melanogaster have been pivotal in uncovering how the immune response is regulated by both endocrine and metabolic signalling systems, and how the immune response modifies these systems as part of a homeostatic circuit. In this Review, we briefly summarize microbial recognition and antiviral immunity in D. melanogaster, and we highlight recent studies that have explored the effects of organism-wide regulation of the immune response and, conversely, the effects of the immune response on organism physiology.

Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity.

PubMed

Tauber, Svantje; Lauber, Beatrice A; Paulsen, Katrin; Layer, Liliana E; Lehmann, Martin; Hauschild, Swantje; Shepherd, Naomi R; Polzer, Jennifer; Segerer, Jürgen; Thiel, Cora S; Ullrich, Oliver

2017-01-01

The immune system is one of the most affected systems of the human body during space flight. The cells of the immune system are exceptionally sensitive to microgravity. Thus, serious concerns arise, whether space flight associated weakening of the immune system ultimately precludes the expansion of human presence beyond the Earth's orbit. For human space flight, it is an urgent need to understand the cellular and molecular mechanisms by which altered gravity influences and changes the functions of immune cells. The CELLBOX-PRIME (= CellBox-Primary Human Macrophages in Microgravity Environment) experiment investigated for the first time microgravity-associated long-term alterations in primary human macrophages, one of the most important effector cells of the immune system. The experiment was conducted in the U.S. National Laboratory on board of the International Space Station ISS using the NanoRacks laboratory and Biorack type I standard CELLBOX EUE type IV containers. Upload and download were performed with the SpaceX CRS-3 and the Dragon spaceship on April 18th, 2014 / May 18th, 2014. Surprisingly, primary human macrophages exhibited neither quantitative nor structural changes of the actin and vimentin cytoskeleton after 11 days in microgravity when compared to 1g controls. Neither CD18 or CD14 surface expression were altered in microgravity, however ICAM-1 expression was reduced. The analysis of 74 metabolites in the cell culture supernatant by GC-TOF-MS, revealed eight metabolites with significantly different quantities when compared to 1g controls. In particular, the significant increase of free fucose in the cell culture supernatant was associated with a significant decrease of cell surface-bound fucose. The reduced ICAM-1 expression and the loss of cell surface-bound fucose may contribute to functional impairments, e.g. the activation of T cells, migration and activation of the innate immune response. We assume that the surprisingly small and non-significant cytoskeletal alterations represent a stable "steady state" after adaptive processes are initiated in the new microgravity environment. Due to the utmost importance of the human macrophage system for the elimination of pathogens and the clearance of apoptotic cells, its apparent robustness to a low gravity environment is crucial for human health and performance during long-term space missions.

Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity

PubMed Central

Tauber, Svantje; Lauber, Beatrice A.; Paulsen, Katrin; Layer, Liliana E.; Lehmann, Martin; Hauschild, Swantje; Shepherd, Naomi R.; Polzer, Jennifer; Segerer, Jürgen; Thiel, Cora S.

2017-01-01

The immune system is one of the most affected systems of the human body during space flight. The cells of the immune system are exceptionally sensitive to microgravity. Thus, serious concerns arise, whether space flight associated weakening of the immune system ultimately precludes the expansion of human presence beyond the Earth's orbit. For human space flight, it is an urgent need to understand the cellular and molecular mechanisms by which altered gravity influences and changes the functions of immune cells. The CELLBOX-PRIME (= CellBox-Primary Human Macrophages in Microgravity Environment) experiment investigated for the first time microgravity-associated long-term alterations in primary human macrophages, one of the most important effector cells of the immune system. The experiment was conducted in the U.S. National Laboratory on board of the International Space Station ISS using the NanoRacks laboratory and Biorack type I standard CELLBOX EUE type IV containers. Upload and download were performed with the SpaceX CRS-3 and the Dragon spaceship on April 18th, 2014 / May 18th, 2014. Surprisingly, primary human macrophages exhibited neither quantitative nor structural changes of the actin and vimentin cytoskeleton after 11 days in microgravity when compared to 1g controls. Neither CD18 or CD14 surface expression were altered in microgravity, however ICAM-1 expression was reduced. The analysis of 74 metabolites in the cell culture supernatant by GC–TOF–MS, revealed eight metabolites with significantly different quantities when compared to 1g controls. In particular, the significant increase of free fucose in the cell culture supernatant was associated with a significant decrease of cell surface–bound fucose. The reduced ICAM-1 expression and the loss of cell surface–bound fucose may contribute to functional impairments, e.g. the activation of T cells, migration and activation of the innate immune response. We assume that the surprisingly small and non-significant cytoskeletal alterations represent a stable “steady state” after adaptive processes are initiated in the new microgravity environment. Due to the utmost importance of the human macrophage system for the elimination of pathogens and the clearance of apoptotic cells, its apparent robustness to a low gravity environment is crucial for human health and performance during long-term space missions. PMID:28419128

Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria

PubMed Central

Lee, Ki-Young; Lee, Bong-Jin

2016-01-01

Bacterial toxin–antitoxin (TA) systems have received increasing attention for their diverse identities, structures, and functional implications in cell cycle arrest and survival against environmental stresses such as nutrient deficiency, antibiotic treatments, and immune system attacks. In this review, we describe the biological functions and the auto-regulatory mechanisms of six different types of TA systems, among which the type II TA system has been most extensively studied. The functions of type II toxins include mRNA/tRNA cleavage, gyrase/ribosome poison, and protein phosphorylation, which can be neutralized by their cognate antitoxins. We mainly explore the similar but divergent structures of type II TA proteins from 12 important pathogenic bacteria, including various aspects of protein–protein interactions. Accumulating knowledge about the structure–function correlation of TA systems from pathogenic bacteria has facilitated a novel strategy to develop antibiotic drugs that target specific pathogens. These molecules could increase the intrinsic activity of the toxin by artificially interfering with the intermolecular network of the TA systems. PMID:27782085

Synthetic immunology: modulating the human immune system.

PubMed

Geering, Barbara; Fussenegger, Martin

2015-02-01

Humans have manipulated the immune system to dampen or boost the immune response for thousands of years. As our understanding of fundamental immunology and biotechnological methodology accumulates, we can capitalize on this combined knowledge to engineer biological devices with the aim of rationally manipulating the immune response. We address therapeutic approaches based on the principles of synthetic immunology that either ameliorate disorders of the immune system by interfering with the immune response, or improve diverse pathogenic conditions by exploiting immune cell effector functions. We specifically highlight synthetic proteins investigated in preclinical and clinical trials, summarize studies that have used engineered immune cells, and finish with a discussion of possible future therapeutic concepts. Copyright © 2014 Elsevier Ltd. All rights reserved.

The deconvolution of complex spectra by artificial immune system

NASA Astrophysics Data System (ADS)

Galiakhmetova, D. I.; Sibgatullin, M. E.; Galimullin, D. Z.; Kamalova, D. I.

2017-11-01

An application of the artificial immune system method for decomposition of complex spectra is presented. The results of decomposition of the model contour consisting of three components, Gaussian contours, are demonstrated. The method of artificial immune system is an optimization method, which is based on the behaviour of the immune system and refers to modern methods of search for the engine optimization.

Immune System Activation and Depression: Roles of Serotonin in the Central Nervous System and Periphery.

PubMed

Robson, Matthew J; Quinlan, Meagan A; Blakely, Randy D

2017-05-17

Serotonin (5-hydroxytryptamine, 5-HT) has long been recognized as a key contributor to the regulation of mood and anxiety and is strongly associated with the etiology of major depressive disorder (MDD). Although more known for its roles within the central nervous system (CNS), 5-HT is recognized to modulate several key aspects of immune system function that may contribute to the development of MDD. Copious amounts of research have outlined a connection between alterations in immune system function, inflammation status, and MDD. Supporting this connection, peripheral immune activation results in changes in the function and/or expression of many components of 5-HT signaling that are associated with depressive-like phenotypes. How 5-HT is utilized by the immune system to effect CNS function and ultimately behaviors related to depression is still not well understood. This Review summarizes the evidence that immune system alterations related to depression affect CNS 5-HT signaling that can alter MDD-relevant behaviors and that 5-HT regulates immune system signaling within the CNS and periphery. We suggest that targeting the interrelationships between immune and 5-HT signaling may provide more effective treatments for subsets of those suffering from inflammation-associated MDD.

Role of the immune system in cardiac tissue damage and repair following myocardial infarction.

PubMed

Saparov, Arman; Ogay, Vyacheslav; Nurgozhin, Talgat; Chen, William C W; Mansurov, Nurlan; Issabekova, Assel; Zhakupova, Jamilya

2017-09-01

The immune system plays a crucial role in the initiation, development, and resolution of inflammation following myocardial infarction (MI). The lack of oxygen and nutrients causes the death of cardiomyocytes and leads to the exposure of danger-associated molecular patterns that are recognized by the immune system to initiate inflammation. At the initial stage of post-MI inflammation, the immune system further damages cardiac tissue to clear cell debris. The excessive production of reactive oxygen species (ROS) by immune cells and the inability of the anti-oxidant system to neutralize ROS cause oxidative stress that further aggravates inflammation. On the other hand, the cells of both innate and adaptive immune system and their secreted factors are critically instrumental in the very dynamic and complex processes of regulating inflammation and mediating cardiac repair. It is important to decipher the balance between detrimental and beneficial effects of the immune system in MI. This enables us to identify better therapeutic targets for reducing the infarct size, sustaining the cardiac function, and minimizing the likelihood of heart failure. This review discusses the role of both innate and adaptive immune systems in cardiac tissue damage and repair in experimental models of MI.

Anti-Immune Strategies of Pathogenic Fungi

PubMed Central

Marcos, Caroline M.; de Oliveira, Haroldo C.; de Melo, Wanessa de Cássia M. Antunes; da Silva, Julhiany de Fátima; Assato, Patrícia A.; Scorzoni, Liliana; Rossi, Suélen A.; de Paula e Silva, Ana C. A.; Mendes-Giannini, Maria J. S.; Fusco-Almeida, Ana M.

2016-01-01

Pathogenic fungi have developed many strategies to evade the host immune system. Multiple escape mechanisms appear to function together to inhibit attack by the various stages of both the adaptive and the innate immune response. Thus, after entering the host, such pathogens fight to overcome the immune system to allow their survival, colonization and spread to different sites of infection. Consequently, the establishment of a successful infectious process is closely related to the ability of the pathogen to modulate attack by the immune system. Most strategies employed to subvert or exploit the immune system are shared among different species of fungi. In this review, we summarize the main strategies employed for immune evasion by some of the major pathogenic fungi. PMID:27896220

Effects of engineered nanoparticles on the innate immune system.

PubMed

Liu, Yuanchang; Hardie, Joseph; Zhang, Xianzhi; Rotello, Vincent M

2017-12-01

Engineered nanoparticles (NPs) have broad applications in industry and nanomedicine. When NPs enter the body, interactions with the immune system are unavoidable. The innate immune system, a non-specific first line of defense against potential threats to the host, immediately interacts with introduced NPs and generates complicated immune responses. Depending on their physicochemical properties, NPs can interact with cells and proteins to stimulate or suppress the innate immune response, and similarly activate or avoid the complement system. NPs size, shape, hydrophobicity and surface modification are the main factors that influence the interactions between NPs and the innate immune system. In this review, we will focus on recent reports about the relationship between the physicochemical properties of NPs and their innate immune response, and their applications in immunotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunoevasive Aspergillus virulence factors.

PubMed

Chotirmall, Sanjay H; Mirkovic, Bojana; Lavelle, Gillian M; McElvaney, Noel G

2014-12-01

Individuals with structural lung disease or defective immunity are predisposed to Aspergillus-associated disease. Manifestations range from allergic to cavitary or angio-invasive syndromes. Despite daily spore inhalation, immunocompetence facilitates clearance through initiation of innate and adaptive host responses. These include mechanical barriers, phagocyte activation, antimicrobial peptide release and pattern recognition receptor activation. Adaptive responses include Th1 and Th2 approaches. Understanding Aspergillus virulence mechanisms remains critical to the development of effective research and treatment strategies to counteract the fungi. Major virulence factors relate to fungal structure, protease release and allergens; however, mechanisms utilized to evade immune recognition continue to be important in establishing infection. These include the fungal rodlet layer, dihydroxynaphthalene-melanin, detoxifying systems for reactive oxygen species and toxin release. One major immunoevasive toxin, gliotoxin, plays a key role in mediating Aspergillus-associated colonization in the context of cystic fibrosis. Here, it down-regulates vitamin D receptor expression which following itraconazole therapy is rescued concurrent with decreased Th2 cytokine (IL-5 and IL-13) concentrations in the CF airway. This review focuses on the interaction between Aspergillus pathogenic mechanisms, host immune responses and the immunoevasive strategies employed by the organism during disease states such as that observed in cystic fibrosis.

Pneumococcal Capsules and Their Types: Past, Present, and Future

PubMed Central

Geno, K. Aaron; Gilbert, Gwendolyn L.; Song, Joon Young; Skovsted, Ian C.; Klugman, Keith P.; Jones, Christopher; Konradsen, Helle B.

2015-01-01

SUMMARY Streptococcus pneumoniae (the pneumococcus) is an important human pathogen. Its virulence is largely due to its polysaccharide capsule, which shields it from the host immune system, and because of this, the capsule has been extensively studied. Studies of the capsule led to the identification of DNA as the genetic material, identification of many different capsular serotypes, and identification of the serotype-specific nature of protection by adaptive immunity. Recent studies have led to the determination of capsular polysaccharide structures for many serotypes using advanced analytical technologies, complete elucidation of genetic basis for the capsular types, and the development of highly effective pneumococcal conjugate vaccines. Conjugate vaccine use has altered the serotype distribution by either serotype replacement or switching, and this has increased the need to serotype pneumococci. Due to great advances in molecular technologies and our understanding of the pneumococcal genome, molecular approaches have become powerful tools to predict pneumococcal serotypes. In addition, more-precise and -efficient serotyping methods that directly detect polysaccharide structures are emerging. These improvements in our capabilities will greatly enhance future investigations of pneumococcal epidemiology and diseases and the biology of colonization and innate immunity to pneumococcal capsules. PMID:26085553

Pneumococcal Capsules and Their Types: Past, Present, and Future.

PubMed

Geno, K Aaron; Gilbert, Gwendolyn L; Song, Joon Young; Skovsted, Ian C; Klugman, Keith P; Jones, Christopher; Konradsen, Helle B; Nahm, Moon H

2015-07-01

Streptococcus pneumoniae (the pneumococcus) is an important human pathogen. Its virulence is largely due to its polysaccharide capsule, which shields it from the host immune system, and because of this, the capsule has been extensively studied. Studies of the capsule led to the identification of DNA as the genetic material, identification of many different capsular serotypes, and identification of the serotype-specific nature of protection by adaptive immunity. Recent studies have led to the determination of capsular polysaccharide structures for many serotypes using advanced analytical technologies, complete elucidation of genetic basis for the capsular types, and the development of highly effective pneumococcal conjugate vaccines. Conjugate vaccine use has altered the serotype distribution by either serotype replacement or switching, and this has increased the need to serotype pneumococci. Due to great advances in molecular technologies and our understanding of the pneumococcal genome, molecular approaches have become powerful tools to predict pneumococcal serotypes. In addition, more-precise and -efficient serotyping methods that directly detect polysaccharide structures are emerging. These improvements in our capabilities will greatly enhance future investigations of pneumococcal epidemiology and diseases and the biology of colonization and innate immunity to pneumococcal capsules. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Annotation and Classification of CRISPR-Cas Systems

PubMed Central

Makarova, Kira S.; Koonin, Eugene V.

2018-01-01

The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas (CRISPR-associated proteins) is a prokaryotic adaptive immune system that is represented in most archaea and many bacteria. Among the currently known prokaryotic defense systems, the CRISPR-Cas genomic loci show unprecedented complexity and diversity. Classification of CRISPR-Cas variants that would capture their evolutionary relationships to the maximum possible extent is essential for comparative genomic and functional characterization of this theoretically and practically important system of adaptive immunity. To this end, a multipronged approach has been developed that combines phylogenetic analysis of the conserved Cas proteins with comparison of gene repertoires and arrangements in CRISPR-Cas loci. This approach led to the current classification of CRISPR-Cas systems into three distinct types and ten subtypes for each of which signature genes have been identified. Comparative genomic analysis of the CRISPR-Cas systems in new archaeal and bacterial genomes performed over the 3 years elapsed since the development of this classification makes it clear that new types and subtypes of CRISPR-Cas need to be introduced. Moreover, this classification system captures only part of the complexity of CRISPR-Cas organization and evolution, due to the intrinsic modularity and evolutionary mobility of these immunity systems, resulting in numerous recombinant variants. Moreover, most of the cas genes evolve rapidly, complicating the family assignment for many Cas proteins and the use of family profiles for the recognition of CRISPR-Cas subtype signatures. Further progress in the comparative analysis of CRISPR-Cas systems requires integration of the most sensitive sequence comparison tools, protein structure comparison, and refined approaches for comparison of gene neighborhoods. PMID:25981466

Annotation and Classification of CRISPR-Cas Systems.

PubMed

Makarova, Kira S; Koonin, Eugene V

2015-01-01

The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas (CRISPR-associated proteins) is a prokaryotic adaptive immune system that is represented in most archaea and many bacteria. Among the currently known prokaryotic defense systems, the CRISPR-Cas genomic loci show unprecedented complexity and diversity. Classification of CRISPR-Cas variants that would capture their evolutionary relationships to the maximum possible extent is essential for comparative genomic and functional characterization of this theoretically and practically important system of adaptive immunity. To this end, a multipronged approach has been developed that combines phylogenetic analysis of the conserved Cas proteins with comparison of gene repertoires and arrangements in CRISPR-Cas loci. This approach led to the current classification of CRISPR-Cas systems into three distinct types and ten subtypes for each of which signature genes have been identified. Comparative genomic analysis of the CRISPR-Cas systems in new archaeal and bacterial genomes performed over the 3 years elapsed since the development of this classification makes it clear that new types and subtypes of CRISPR-Cas need to be introduced. Moreover, this classification system captures only part of the complexity of CRISPR-Cas organization and evolution, due to the intrinsic modularity and evolutionary mobility of these immunity systems, resulting in numerous recombinant variants. Moreover, most of the cas genes evolve rapidly, complicating the family assignment for many Cas proteins and the use of family profiles for the recognition of CRISPR-Cas subtype signatures. Further progress in the comparative analysis of CRISPR-Cas systems requires integration of the most sensitive sequence comparison tools, protein structure comparison, and refined approaches for comparison of gene neighborhoods.

The structure of cytomegalovirus immune modulator UL141 highlights structural Ig-fold versatility for receptor binding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nemčovičová, Ivana; Slovak Academy of Sciences, Dúbravská cesta 9, SK 84505 Bratislava; Zajonc, Dirk M., E-mail: dzajonc@liai.org

2014-03-01

The crystal structure of Human cytomegalovirus immune modulator UL141 was solved at 3.25 Å resolution. Here, a detailed analysis of its intimate dimerization interface and the biophysical properties of its receptor (TRAIL-R2 and CD155) binding interactions are presented. Natural killer (NK) cells are critical components of the innate immune system as they rapidly detect and destroy infected cells. To avoid immune recognition and to allow long-term persistence in the host, Human cytomegalovirus (HCMV) has evolved a number of genes to evade or inhibit immune effector pathways. In particular, UL141 can inhibit cell-surface expression of both the NK cell-activating ligand CD155more » as well as the TRAIL death receptors (TRAIL-R1 and TRAIL-R2). The crystal structure of unliganded HCMV UL141 refined to 3.25 Å resolution allowed analysis of its head-to-tail dimerization interface. A ‘dimerization-deficient’ mutant of UL141 (ddUL141) was further designed, which retained the ability to bind to TRAIL-R2 or CD155 while losing the ability to cross-link two receptor monomers. Structural comparison of unliganded UL141 with UL141 bound to TRAIL-R2 further identified a mobile loop that makes intimate contacts with TRAIL-R2 upon receptor engagement. Superposition of the Ig-like domain of UL141 on the CD155 ligand T-cell immunoreceptor with Ig and ITIM domains (TIGIT) revealed that UL141 can potentially engage CD155 similar to TIGIT by using the C′C′′ and GF loops. Further mutations in the TIGIT binding site of CD155 (Q63R and F128R) abrogated UL141 binding, suggesting that the Ig-like domain of UL141 is a viral mimic of TIGIT, as it targets the same binding site on CD155 using similar ‘lock-and-key’ interactions. Sequence alignment of the UL141 gene and its orthologues also showed conservation in this highly hydrophobic (L/A)X{sub 6}G ‘lock’ motif for CD155 binding as well as conservation of the TRAIL-R2 binding patches, suggesting that these host–receptor interactions are evolutionary conserved.« less

Mind-body hypnotic imagery in the treatment of auto-immune disorders.

PubMed

Torem, Moshe S

2007-10-01

For many years Western Medicine has considered the immune system to be separate and independent from the central nervous system. However, significant scientific advances and research discoveries that occurred during the past 50 years have presented additional facts that the immune system does interact with the central nervous system with mutual influence. This article provides a systematic review of the literature on the connection between the brain and the immune system and its clinical implications. It then provides a rational foundation for the role of using hypnosis and imagery to therapeutically influence the immune system. Five case examples are provided with illustrated instructions for clinicians on how hypnosis and imagery may be utilized in the treatment of patients with auto-immune disorders. Suggestions for future research in this field are included.

At the crossroads between tolerance and aggression: Revisiting the "layered immune system" hypothesis.

PubMed

Mold, Jeff E; McCune, Joseph M

2011-04-01

"We do not grow absolutely, chronologically. We grow sometimes in one dimension, and not in another; unevenly. We grow partially. We are relative. We are mature in one realm, childish in another. The past, present and future mingle and pull us backward, forward, or fix us in the present. We are made up of layers, cells, constellations."-Anaïs NinIt has long been recognized that the developing immune system exhibits certain peculiarities when compared to the adult immune system. Nonetheless, many still regard the fetal immune system as simply being an immature version of the adult immune system. Here we discuss historical evidence as well as recent findings, which suggest that the human immune system may develop in distinct layers with specific functions at different stages of development.

The people factor: An analysis of the human resources landscape for immunization supply chain management.

PubMed

Kasonde, Musonda; Steele, Pamela

2017-04-19

Human resources is the backbone of any system and the key enabler for all other functions to effectively perform. This is no different with the Immunization Supply Chain, more so in todays' complex operating environment with the increasing strain caused by new vaccines and expanding immunization programmes (Source: WHO, UNICEF). In order to drive the change that is required for sustainability and continuous improvement, every immunization supply chain needs an effective leader. A dedicated and competent immunization supply chain leader with adequate numbers of skilled, accountable, motivated and empowered personnel at all levels of the health system to overcome existing and emerging immunization supply chain (ISC) challenges. Without an effective supply chain leader supported by capable and motivated staff, none of the interventions designed to strengthen the supply chain can be effective or sustainable (Source: Gavi Alliance SC Strategy 2014). This landscape analysis was preceded by an HR Evidence Review (March 2014) and has served to inform global partner strategies and country activities, as well as highlight where most support is required. The study also aimed to define the status quo in order to create some form of baseline against which to measure the impact of interventions related to HR going forward. The analysis was comprised of a comprehensive desk review, a survey of 40 respondents from 32 countries and consultations with ISC practitioners in several forums. The findings highlight key areas that should inform the pillars of a HR capacity development plan. At the same time, it revealed that there are some positive examples of where countries are actively addressing some of the issues identified and putting in place mechanisms and structures to optimize the SC function. Copyright © 2017. Published by Elsevier Ltd.

Perspectives of Immunization Program Managers on 2009-10 H1N1 Vaccination in the United States: A National Survey

PubMed Central

Seib, Katherine; Wells, Katelyn; Hannan, Claire; Orenstein, Walter A.; Whitney, Ellen A. S.; Hinman, Alan R.; Berkelman, Ruth L.; Omer, Saad B.

2012-01-01

Abstract In June and July 2010, we conducted a national internet-based survey of 64 city, state, and territorial immunization program managers (IPMs) to assess their experiences in managing the 2009-10 H1N1 influenza vaccination campaign. Fifty-four (84%) of the managers or individuals responsible for an immunization program responded to the survey. To manage the campaign, 76% indicated their health department activated an incident command system (ICS) and 49% used an emergency operations center (EOC). Forty percent indicated they shared the leadership of the campaign with their state-level emergency preparedness program. The managers' perceptions of the helpfulness of the emergency preparedness staff was higher when they had collaborated with the emergency preparedness program on actual or simulated mass vaccination events within the previous 2 years. Fifty-seven percent found their pandemic influenza plan helpful, and those programs that mandated that vaccine providers enter data into their jurisdiction's immunization information system (IIS) were more likely than those who did not mandate data entry to rate their IIS as valuable for facilitating registration of nontraditional providers (42% vs. 25%, p<0.05) and tracking recalled influenza vaccine (50% vs. 38%, p<0.05). Results suggest that ICS and EOC structures, pandemic influenza plans, collaborations with emergency preparedness partners during nonemergencies, and expanded use of IIS can enhance immunization programs' ability to successfully manage a large-scale vaccination campaign. Maintaining the close working relationships developed between state-level immunization and emergency preparedness programs during the H1N1 influenza vaccination campaign will be especially important as states prepare for budget cuts in the coming years. PMID:22360580

A human tissue-based functional assay platform to evaluate the immune function impact of small molecule inhibitors that target the immune system.

PubMed

St Pierre, Cristina; Guo, Jane; Shin, John D; Engstrom, Laura W; Lee, Hyun-Hee; Herbert, Alan; Surdi, Laura; Baker, James; Salmon, Michael; Shah, Sanjiv; Ellis, J Michael; Houshyar, Hani; Crackower, Michael A; Kleinschek, Melanie A; Jones, Dallas C; Hicks, Alexandra; Zaller, Dennis M; Alves, Stephen E; Ramadas, Ravisankar A

2017-01-01

While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the 'immune fingerprint' of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer. Since the mechanistic investigation of pharmacological modulators in a drug discovery setting is largely compound- and mechanism-centric but not comprehensive in terms of immune system impact, we developed a human tissue based functional assay platform to evaluate the impact of pharmacological modulators on a range of innate and adaptive immune functions. Here, we demonstrate that it is possible to generate a qualitative and quantitative immune system impact of pharmacological modulators, which might help better understand and predict the benefit-risk profiles of these compounds in the treatment of immune disorders.

Gap junction-mediated intercellular communication in the immune system.

PubMed

Neijssen, Joost; Pang, Baoxu; Neefjes, Jacques

2007-01-01

Immune cells are usually considered non-attached blood cells, which would exclude the formation of gap junctions. This is a misconception since many immune cells express connexin 43 (Cx43) and other connexins and are often residing in tissue. The role of gap junctions is largely ignored by immunologists as is the immune system in the field of gap junction research. Here, the current knowledge of the distribution of connexins and the function of gap junctions in the immune system is discussed. Gap junctions appear to play many roles in antibody productions and specific immune responses and may be important in sensing danger in tissue by the immune system. Gap junctions not only transfer electrical and metabolical but also immunological information in the form of peptides for a process called cross-presentation. This is essential for proper immune responses to viruses and possibly tumours. Until now only 40 research papers on gap junctions in the immune system appeared and this will almost certainly expand with the increased mutual interest between the fields of immunology and gap junction research.

The effects of early life adversity on the immune system.

PubMed

Elwenspoek, Martha M C; Kuehn, Annette; Muller, Claude P; Turner, Jonathan D

2017-08-01

Early life adversity (ELA) is associated with a higher risk for diseases in adulthood. Although the pathophysiological effects of ELA are varied, there may be a unifying role for the immune system in all of the long-term pathologies such as chronic inflammatory disorders (autoimmune diseases, allergy, and asthma). Recently, significant efforts have been made to elucidate the long-term effects ELA has on immune function, as well as the mechanisms underlying these immune changes. In this review, we focus on data from human studies investigating immune parameters in relation to post-natal adverse experiences. We describe the current understanding of the 'ELA immune phenotype', characterized by inflammation, impairment of the cellular immune system, and immunosenescence. However, at present, data addressing specific immune functions are limited and there is a need for high-quality, well powered, longitudinal studies to unravel cause from effect. Besides the immune system, also the stress system and health behaviors are altered in ELA. We discuss probable underlying mechanisms based on epigenetic programming that could explain the ELA immune phenotype and whether this is a direct effect of immune programming or an indirect consequence of changes in behavior or stress reactivity. Understanding the underlying mechanisms will help define effective strategies to prevent or counteract negative ELA-associated outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Stability of Lentiviral Vector-Mediated Transgene Expression in the Brain in the Presence of Systemic Antivector Immune Responses

PubMed Central

ABORDO-ADESIDA, EVELYN; FOLLENZI, ANTONIA; BARCIA, CARLOS; SCIASCIA, SANDRA; CASTRO, MARIA G.; NALDINI, LUIGI; LOWENSTEIN, PEDRO R.

2009-01-01

Lentiviral vectors are promising tools for gene therapy in the CNS. It is therefore important to characterize their interactions with the immune system in the CNS. This work characterizes transgene expression and brain inflammation in the presence or absence of immune responses generated after systemic immunization with lentiviral vectors. We characterized transduction with SIN-LV vectors in the CNS. A dose—response curve using SIN-LV-GFP demonstrated detectable transgene expression in the striatum at a dose of 102, and maximum expression at 106, transducing units of lentiviral vector, with minimal increase in inflammatory markers between the lowest and highest dose of vector injected. Our studies demonstrate that injection of a lentiviral vector into the CNS did not cause a measurable inflammatory response. Systemic immunization after CNS injection, with the lentiviral vector expressing the same transgene as a vector injected into the CNS, caused a decrease in transgene expression in the CNS, concomitantly with an infiltration of inflammatory cells into the CNS parenchyma at the injection site. However, peripheral immunization with a lentiviral vector carrying a different transgene did not diminish transgene expression, or cause CNS inflammation. Systemic immunization preceding injection of lentiviral vectors into the CNS determined that preexisting antilentiviral immunity, regardless of the transgene, did not affect transgene expression. Furthermore, we showed that the transgene, but not the virion or vector components, is responsible for providing antigenic epitopes to the activated immune system, on systemic immunization with lentivirus. Low immunogenicity and prolonged transgene expression in the presence of preexisting lentiviral immunity are encouraging data for the future use of lentiviral vectors in CNS gene therapy. In summary, the lentiviral vectors tested induced undetectable activation of innate immune responses, and stimulation of adaptive immune responses against lentiviral vectors was effective in causing a decrease in transgene expression only if the immune response was directed against the transgene. A systemic immune response against vector components alone did not cause brain inflammation, possibly because vector-derived epitopes were not being presented in the CNS. PMID:15960605

Structural and Functional Analysis of DDX41: a bispecific immune receptor for DNA and cyclic dinucleotide

PubMed Central

Omura, Hiroki; Oikawa, Daisuke; Nakane, Takanori; Kato, Megumi; Ishii, Ryohei; Ishitani, Ryuichiro; Tokunaga, Fuminori; Nureki, Osamu

2016-01-01

In the innate immune system, pattern recognition receptors (PRRs) specifically recognize ligands derived from bacteria or viruses, to trigger the responsible downstream pathways. DEAD box protein 41 (DDX41) is an intracellular PRR that triggers the downstream pathway involving the adapter STING, the kinase TBK1, and the transcription factor IRF3, to activate the type I interferon response. DDX41 is unique in that it recognizes two different ligands; i.e., double-stranded DNA (dsDNA) and cyclic dinucleotides (CDN), via its DEAD domain. However, the structural basis for the ligand recognition by the DDX41 DEAD domain has remained elusive. Here, we report two crystal structures of the DDX41 DEAD domain in apo forms, at 1.5 and 2.2 Å resolutions. A comparison of the two crystal structures revealed the flexibility in the ATP binding site, suggesting its formation upon ATP binding. Structure-guided functional analyses in vitro and in vivo demonstrated the overlapped binding surface for dsDNA and CDN, which is distinct from the ATP-binding site. We propose that the structural rearrangement of the ATP binding site is crucial for the release of ADP, enabling the fast turnover of DDX41 for the dsDNA/CDN-induced STING activation pathway. PMID:27721487

Interplay Between Innate Immunity and the Plant Microbiota.

PubMed

Hacquard, Stéphane; Spaepen, Stijn; Garrido-Oter, Ruben; Schulze-Lefert, Paul

2017-08-04

The innate immune system of plants recognizes microbial pathogens and terminates their growth. However, recent findings suggest that at least one layer of this system is also engaged in cooperative plant-microbe interactions and influences host colonization by beneficial microbial communities. This immune layer involves sensing of microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) that initiate quantitative immune responses to control host-microbial load, whereas diversification of MAMPs and PRRs emerges as a mechanism that locally sculpts microbial assemblages in plant populations. This suggests a more complex microbial management role of the innate immune system for controlled accommodation of beneficial microbes and in pathogen elimination. The finding that similar molecular strategies are deployed by symbionts and pathogens to dampen immune responses is consistent with this hypothesis but implies different selective pressures on the immune system due to contrasting outcomes on plant fitness. The reciprocal interplay between microbiota and the immune system likely plays a critical role in shaping beneficial plant-microbiota combinations and maintaining microbial homeostasis.

The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC

PubMed Central

Falcao‐Pires, Ines; Balligand, Jean‐Luc; Bauersachs, Johann; Brutsaert, Dirk; Ciccarelli, Michele; Dawson, Dana; de Windt, Leon J.; Giacca, Mauro; Hamdani, Nazha; Hilfiker‐Kleiner, Denise; Hirsch, Emilio; Leite‐Moreira, Adelino; Mayr, Manuel; Thum, Thomas; Tocchetti, Carlo G.; van der Velden, Jolanda; Varricchi, Gilda; Heymans, Stephane

2018-01-01

Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies. PMID:29333691

Recent Advances in Aptamers Targeting Immune System.

PubMed

Hu, Piao-Ping

2017-02-01

The immune system plays important role in protecting the organism by recognizing non-self molecules from pathogen such as bacteria, parasitic worms, and viruses. When the balance of the host defense system is disturbed, immunodeficiency, autoimmunity, and inflammation occur. Nucleic acid aptamers are short single-stranded DNA (ssDNA) or RNA ligands that interact with complementary molecules with high specificity and affinity. Aptamers that target the molecules involved in immune system to modulate their function have great potential to be explored as new diagnostic and therapeutic agents for immune disorders. This review summarizes recent advances in the development of aptamers targeting immune system. The selection of aptamers with superior chemical and biological characteristics will facilitate their application in the diagnosis and treatment of immune disorders.

Lipid Rafts in Mast Cell Biology

PubMed Central

Silveira e Souza, Adriana Maria Mariano; Mazucato, Vivian Marino; Jamur, Maria Célia; Oliver, Constance

2011-01-01

Mast cells have long been recognized to have a direct and critical role in allergic and inflammatory reactions. In allergic diseases, these cells exert both local and systemic responses, including allergic rhinitis and anaphylaxis. Mast cell mediators are also related to many chronic inflammatory conditions. Besides the roles in pathological conditions, the biological functions of mast cells include roles in innate immunity, involvement in host defense mechanisms against parasites, immunomodulation of the immune system, tissue repair, and angiogenesis. Despite their growing significance in physiological and pathological conditions, much still remains to be learned about mast cell biology. This paper presents evidence that lipid rafts or raft components modulate many of the biological processes in mast cells, such as degranulation and endocytosis, play a role in mast cell development and recruitment, and contribute to the overall preservation of mast cell structure and organization. PMID:21490812

How Psychological States Affect the Immune System: Implications for Interventions in the Context of HIV.

ERIC Educational Resources Information Center

Littrell, Jill

1996-01-01

Discusses the psychological states associated with enhanced immune system functioning and those associated with suppressed immune functioning. Reviews studies of psychological and behavioral interventions to boost the immune systems of people who are HIV positive. Suggests that group interventions can enhance psychological states associated with…

Ageing and the immune system: focus on macrophages.

PubMed

Linehan, E; Fitzgerald, D C

2015-03-01

A fully functioning immune system is essential in order to maintain good health. However, the immune system deteriorates with advancing age, and this contributes to increased susceptibility to infection, autoimmunity, and cancer in the older population. Progress has been made in identifying age-related defects in the adaptive immune system. In contrast, relatively little research has been carried out on the impact of ageing on the innate immune response. This area requires further research as the innate immune system plays a crucial role in protection against infection and represents a first line of defence. Macrophages are central effector cells of the innate immune system and have many diverse functions. As a result, age-related impairments in macrophage function are likely to have important consequences for the health of the older population. It has been reported that ageing in macrophages impacts on many processes including toll-like receptor signalling, polarisation, phagocytosis, and wound repair. A detailed understanding of the impact of ageing on macrophages is required in order to develop therapeutics that will boost immune responses in the older population.

Neuro-immune interactions in inflammation and host defense: Implications for transplantation.

PubMed

Chavan, Sangeeta S; Ma, Pingchuan; Chiu, Isaac M

2018-03-01

Sensory and autonomic neurons of the peripheral nervous system (PNS) play a critical role in regulating the immune system during tissue inflammation and host defense. Recent studies have identified the molecular mechanisms underlying the bidirectional communication between the nervous system and the immune system. Here, we highlight the studies that demonstrate the importance of the neuro-immune interactions in health and disease. Nociceptor sensory neurons detect immune mediators to produce pain, and release neuropeptides that act on the immune system to regulate inflammation. In parallel, neural reflex circuits including the vagus nerve-based inflammatory reflex are physiological regulators of inflammatory responses and cytokine production. In transplantation, neuro-immune communication could significantly impact the processes of host-pathogen defense, organ rejection, and wound healing. Emerging approaches to target the PNS such as bioelectronics could be useful in improving the outcome of transplantation. Therefore, understanding how the nervous system shapes the immune response could have important therapeutic ramifications for transplantation medicine. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Immune System and Kidney Transplantation.

PubMed

Shrestha, Badri Man

2017-01-01

The immune system recognises a transplanted kidney as foreign body and mounts immune response through cellular and humoral mechanisms leading to acute or chronic rejection, which ultimately results in graft loss. Over the last five decades, there have been significant advances in the understanding of the immune responses to transplanted organs in both experimental and clinical transplant settings. Modulation of the immune response by using immunosuppressive agents has led to successful outcomes after kidney transplantation. The paper provides an overview of the general organisation and function of human immune system, immune response to kidney transplantation, and the current practice of immunosuppressive therapy in kidney transplantation in the United Kingdom.

Immune system and melanoma biology: a balance between immunosurveillance and immune escape.

PubMed

Passarelli, Anna; Mannavola, Francesco; Stucci, Luigia Stefania; Tucci, Marco; Silvestris, Francesco

2017-12-01

Melanoma is one of the most immunogenic tumors and its relationship with host immune system is currently under investigation. Many immunomodulatory mechanisms, favoring melanomagenesis and progression, have been described to interfere with the disablement of melanoma recognition and attack by immune cells resulting in immune resistance and immunosuppression. This knowledge produced therapeutic advantages, such as immunotherapy, aiming to overcome the immune evasion. Here, we review the current advances in cancer immunoediting and focus on melanoma immunology, which involves a dynamic interplay between melanoma and immune system, as well as on effects of "targeted therapies" on tumor microenvironment for combination strategies.

The Unusual Genetics and Biochemistry of Bovine Immunoglobulins.

PubMed

Stanfield, Robyn L; Haakenson, Jeremy; Deiss, Thaddeus C; Criscitiello, Michael F; Wilson, Ian A; Smider, Vaughn V

2018-01-01

Antibodies are the key circulating molecules that have evolved to fight infection by the adaptive immune system of vertebrates. Typical antibodies of most species contain six complementarity-determining regions (CDRs), where the third CDR of the heavy chain (CDR H3) has the greatest diversity and often makes the most significant contact with antigen. Generally, the process of V(D)J recombination produces a vast repertoire of antibodies; multiple V, D, and J gene segments recombine with additional junctional diversity at the V-D and D-J joints, and additional combinatorial possibilities occur through heavy- and light-chain pairing. Despite these processes, the overall structure of the resulting antibody is largely conserved, and binding to antigen occurs predominantly through the CDR loops of the immunoglobulin V domains. Bovines have deviated from this general paradigm by having few VH regions and thus little germline combinatorial diversity, but their antibodies contain long CDR H3 regions, with substantial diversity generated through somatic hypermutation. A subset of the repertoire comprises antibodies with ultralong CDR H3s, which can reach over 70 amino acids in length. Structurally, these unusual antibodies form a β-ribbon "stalk" and disulfide-bonded "knob" that protrude far from the antibody surface. These long CDR H3s allow cows to mount a particularly robust immune response when immunized with viral antigens, particularly to broadly neutralizing epitopes on a stabilized HIV gp140 trimer, which has been a challenge for other species. The unusual genetics and structural biology of cows provide for a unique paradigm for creation of immune diversity and could enable generation of antibodies against especially challenging targets and epitopes. © 2018 Elsevier Inc. All rights reserved.

Cryptosporidium: Infection - Immunocompromised Persons

MedlinePlus

... might be immunocompromised or have a weakened immune system? Examples of persons with weakened immune systems include ... How does cryptosporidiosis affect you if your immune system is severely weakened? In persons with AIDS and ...

1H, 15N, and 13C resonance assignments of the third domain from the S. aureus innate immune evasion protein Eap.

PubMed

Herrera, Alvaro I; Ploscariu, Nicoleta T; Geisbrecht, Brian V; Prakash, Om

2018-04-01

Staphylococcus aureus is a widespread and persistent pathogen of humans and livestock. The bacterium expresses a wide variety of virulence proteins, many of which serve to disrupt the host's innate immune system from recognizing and clearing bacteria with optimal efficiency. The extracellular adherence protein (Eap) is a multidomain protein that participates in various protein-protein interactions that inhibit the innate immune response, including both the complement system (Woehl et al in J Immunol 193:6161-6171, 2014) and Neutrophil Serine Proteases (NSPs) (Stapels et al in Proc Natl Acad Sci USA 111:13187-13192, 2014). The third domain of Eap, Eap3, is an ~ 11 kDa protein that was recently shown to bind complement component C4b (Woehl et al in Protein Sci 26:1595-1608, 2017) and therefore play an essential role in inhibiting the classical and lectin pathways of complement (Woehl et al in J Immunol 193:6161-6171, 2014). Since structural characterization of Eap3 is still incomplete, we acquired a series of 2D and 3D NMR spectra of Eap3 in solution. Here we report the backbone and side-chain 1 H, 15 N, and 13 C resonance assignments of Eap3 and its predicted secondary structure via the TALOS-N server. The assignment data have been deposited in the BMRB data bank under accession number 27087.

Protein phylogenies provide evidence of a radical discontinuity between arthropod and vertebrate immune systems.

PubMed

Hughes, A L

1998-03-01

Protein phylogenies were used to test the hypothesis that aspects of the innate immune system of vertebrates have been conserved since the last common ancestor of vertebrates and arthropods. The phylogeny of lysozymes showed evidence of conservation of function, but phylogenies of seven other protein families did not. Natural resistance-associated macrophage protein, nitric oxide synthetase, and serine protease families all showed a pattern of gene duplication within vertebrates after their divergence from arthropods, giving rise to immune system-expressed genes in vertebrates. Insect hemolin, a member of the immunoglobulin superfamily, was found not to be closely related to members of that family having an immune system role in vertebrates; rather, it appeared most closely related to both arthropod and vertebrate molecules expressed in the nervous system. Thus, hemolin seems to have evolved its role independently in insects, probably through duplication of a neuroglian-like ancestor. Furthermore, vertebrate immune system-expressed serpins, chitinases, and pentraxins were found to lack orthologous relationships with arthropod members of the same families also functioning in immunity. Therefore members of these families have evolved immune system functions independently in the two phyla. It is now widely recognized that the specific immune system of vertebrates has no counterpart in invertebrates; these phylogenetic analyses suggest that there is a similar evolutionary discontinuity with respect to innate immunity as well.

What vaccination studies tell us about immunological memory within the innate immune system of cultured shrimp and crayfish.

PubMed

Chang, Yu-Hsuan; Kumar, Ramya; Ng, Tze Hann; Wang, Han-Ching

2018-03-01

The possibility of immunological memory in invertebrates is a topic that has recently attracted a lot of attention. Today, even vertebrates are known to exhibit innate immune responses that show memory-like properties, and since these responses are triggered by cells that are involved in the innate immune system, it seems that immune specificity and immune memory do not necessarily require the presence of B cells and T cells after all. This kind of immune response has been called "immune priming" or "trained immunity". In this report, we review recent observations and our current understanding of immunological memory within the innate immune system in cultured shrimp and crayfish after vaccination with live vaccine, killed vaccine and subunit vaccines. We also discuss the possible mechanisms involved in this immune response. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dissecting innate immune responses with the tools of systems biology.

PubMed

Smith, Kelly D; Bolouri, Hamid

2005-02-01

Systems biology strives to derive accurate predictive descriptions of complex systems such as innate immunity. The innate immune system is essential for host defense, yet the resulting inflammatory response must be tightly regulated. Current understanding indicates that this system is controlled by complex regulatory networks, which maintain homoeostasis while accurately distinguishing pathogenic infections from harmless exposures. Recent studies have used high throughput technologies and computational techniques that presage predictive models and will be the foundation of a systems level understanding of innate immunity.

Neuroimmunologic aspects of sleep and sleep loss

NASA Technical Reports Server (NTRS)

Rogers, N. L.; Szuba, M. P.; Staab, J. P.; Evans, D. L.; Dinges, D. F.

2001-01-01

The complex and intimate interactions between the sleep and immune systems have been the focus of study for several years. Immune factors, particularly the interleukins, regulate sleep and in turn are altered by sleep and sleep deprivation. The sleep-wake cycle likewise regulates normal functioning of the immune system. Although a large number of studies have focused on the relationship between the immune system and sleep, relatively few studies have examined the effects of sleep deprivation on immune parameters. Studies of sleep deprivation's effects are important for several reasons. First, in the 21st century, various societal pressures require humans to work longer and sleep less. Sleep deprivation is becoming an occupational hazard in many industries. Second, to garner a greater understanding of the regulatory effects of sleep on the immune system, one must understand the consequences of sleep deprivation on the immune system. Significant detrimental effects on immune functioning can be seen after a few days of total sleep deprivation or even several days of partial sleep deprivation. Interestingly, not all of the changes in immune physiology that occur as a result of sleep deprivation appear to be negative. Numerous medical disorders involving the immune system are associated with changes in the sleep-wake physiology--either being caused by sleep dysfunction or being exacerbated by sleep disruption. These disorders include infectious diseases, fibromyalgia, cancers, and major depressive disorder. In this article, we will describe the relationships between sleep physiology and the immune system, in states of health and disease. Interspersed will be proposals for future research that may illuminate the clinical relevance of the relationships between sleeping, sleep loss and immune function in humans. Copyright 2001 by W.B. Saunders Company.

Polymorphic toxin systems: Comprehensive characterization of trafficking modes, processing, mechanisms of action, immunity and ecology using comparative genomics

PubMed Central

2012-01-01

Background Proteinaceous toxins are observed across all levels of inter-organismal and intra-genomic conflicts. These include recently discovered prokaryotic polymorphic toxin systems implicated in intra-specific conflicts. They are characterized by a remarkable diversity of C-terminal toxin domains generated by recombination with standalone toxin-coding cassettes. Prior analysis revealed a striking diversity of nuclease and deaminase domains among the toxin modules. We systematically investigated polymorphic toxin systems using comparative genomics, sequence and structure analysis. Results Polymorphic toxin systems are distributed across all major bacterial lineages and are delivered by at least eight distinct secretory systems. In addition to type-II, these include type-V, VI, VII (ESX), and the poorly characterized “Photorhabdus virulence cassettes (PVC)”, PrsW-dependent and MuF phage-capsid-like systems. We present evidence that trafficking of these toxins is often accompanied by autoproteolytic processing catalyzed by HINT, ZU5, PrsW, caspase-like, papain-like, and a novel metallopeptidase associated with the PVC system. We identified over 150 distinct toxin domains in these systems. These span an extraordinary catalytic spectrum to include 23 distinct clades of peptidases, numerous previously unrecognized versions of nucleases and deaminases, ADP-ribosyltransferases, ADP ribosyl cyclases, RelA/SpoT-like nucleotidyltransferases, glycosyltranferases and other enzymes predicted to modify lipids and carbohydrates, and a pore-forming toxin domain. Several of these toxin domains are shared with host-directed effectors of pathogenic bacteria. Over 90 families of immunity proteins might neutralize anywhere between a single to at least 27 distinct types of toxin domains. In some organisms multiple tandem immunity genes or immunity protein domains are organized into polyimmunity loci or polyimmunity proteins. Gene-neighborhood-analysis of polymorphic toxin systems predicts the presence of novel trafficking-related components, and also the organizational logic that allows toxin diversification through recombination. Domain architecture and protein-length analysis revealed that these toxins might be deployed as secreted factors, through directed injection, or via inter-cellular contact facilitated by filamentous structures formed by RHS/YD, filamentous hemagglutinin and other repeats. Phyletic pattern and life-style analysis indicate that polymorphic toxins and polyimmunity loci participate in cooperative behavior and facultative ‘cheating’ in several ecosystems such as the human oral cavity and soil. Multiple domains from these systems have also been repeatedly transferred to eukaryotes and their viruses, such as the nucleo-cytoplasmic large DNA viruses. Conclusions Along with a comprehensive inventory of toxins and immunity proteins, we present several testable predictions regarding active sites and catalytic mechanisms of toxins, their processing and trafficking and their role in intra-specific and inter-specific interactions between bacteria. These systems provide insights regarding the emergence of key systems at different points in eukaryotic evolution, such as ADP ribosylation, interaction of myosin VI with cargo proteins, mediation of apoptosis, hyphal heteroincompatibility, hedgehog signaling, arthropod toxins, cell-cell interaction molecules like teneurins and different signaling messengers. Reviewers This article was reviewed by AM, FE and IZ. PMID:22731697

Network intrusion detection by the coevolutionary immune algorithm of artificial immune systems with clonal selection

NASA Astrophysics Data System (ADS)

Salamatova, T.; Zhukov, V.

2017-02-01

The paper presents the application of the artificial immune systems apparatus as a heuristic method of network intrusion detection for algorithmic provision of intrusion detection systems. The coevolutionary immune algorithm of artificial immune systems with clonal selection was elaborated. In testing different datasets the empirical results of evaluation of the algorithm effectiveness were achieved. To identify the degree of efficiency the algorithm was compared with analogs. The fundamental rules based of solutions generated by this algorithm are described in the article.

Who Gets Fungal Infections?

MedlinePlus

... can also happen in people without weak immune systems Fungal infections that are not life-threatening, such ... to cause an infection. People with weak immune systems Infections that happen because a person’s immune system ...

The Immune System and Developmental Programming of Brain and Behavior

PubMed Central

Bilbo, Staci D.; Schwarz, Jaclyn M.

2012-01-01

The brain, endocrine, and immune systems are inextricably linked. Immune molecules have a powerful impact on neuroendocrine function, including hormone-behavior interactions, during health as well as sickness. Similarly, alterations in hormones, such as during stress, can powerfully impact immune function or reactivity. These functional shifts are evolved, adaptive responses that organize changes in behavior and mobilize immune resources, but can also lead to pathology or exacerbate disease if prolonged or exaggerated. The developing brain in particular is exquisitely sensitive to both endogenous and exogenous signals, and increasing evidence suggests the immune system has a critical role in brain development and associated behavioral outcomes for the life of the individual. Indeed, there are associations between many neuropsychiatric disorders and immune dysfunction, with a distinct etiology in neurodevelopment. The goal of this review is to describe the important role of the immune system during brain development, and to discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, mood and cognition. PMID:22982535

Memory and Specificity in the Insect Immune System: Current Perspectives and Future Challenges.

PubMed

Cooper, Dustin; Eleftherianos, Ioannis

2017-01-01

The immune response of a host to a pathogen is typically described as either innate or adaptive. The innate form of the immune response is conserved across all organisms, including insects. Previous and recent research has focused on the nature of the insect immune system and the results imply that the innate immune response of insects is more robust and specific than previously thought. Priming of the insect innate immune system involves the exposure of insects to dead or a sublethal dose of microbes in order to elicit an initial response. Comparing subsequent infections in primed insects to non-primed individuals indicates that the insect innate immune response may possess some of the qualities of an adaptive immune system. Although some studies demonstrate that the protective effects of priming are due to a "loitering" innate immune response, others have presented more convincing elements of adaptivity. While an immune mechanism capable of producing the same degree of recognition specificity as seen in vertebrates has yet to be discovered in insects, a few interesting cases have been identified and discussed.

An immunity-based anomaly detection system with sensor agents.

PubMed

Okamoto, Takeshi; Ishida, Yoshiteru

2009-01-01

This paper proposes an immunity-based anomaly detection system with sensor agents based on the specificity and diversity of the immune system. Each agent is specialized to react to the behavior of a specific user. Multiple diverse agents decide whether the behavior is normal or abnormal. Conventional systems have used only a single sensor to detect anomalies, while the immunity-based system makes use of multiple sensors, which leads to improvements in detection accuracy. In addition, we propose an evaluation framework for the anomaly detection system, which is capable of evaluating the differences in detection accuracy between internal and external anomalies. This paper focuses on anomaly detection in user's command sequences on UNIX-like systems. In experiments, the immunity-based system outperformed some of the best conventional systems.

Weakened Immune System and Adult Vaccination

MedlinePlus

... Adult Vaccination Resources for Healthcare Professionals Weakened Immune System and Adult Vaccination Recommend on Facebook Tweet Share ... with health conditions such as a weakened immune system. If you have cancer or other immunocompromising conditions, ...

[The role of immune system in the control of cancer development and growth].

PubMed

Sütő, Gábor

2016-06-01

The role of immune system is the maintenace of the integritiy of the living organism. The elements of the immune system are connected by several ways forming a complex biological network. This network senses the changes of the inner and outer environment and works out the most effective response against infections and tumors. Dysfunction of the immune system leads to the development of cancer development and chronic inflammatory diseases. Modulation of the checkpoints of the immune system opened new perspecitves in the treatment of rheumatological and oncological diseases as well. Beside the potent antiinflammatory activity, new therapies are able to stimulate anticancer activity of the immune system. The result of these recent developments is a better outcome of malignant diseases, which had an unfavorable outcome in the past. Orv. Hetil., 2016, 157(Suppl. 2), 3-8.

Immunity by equilibrium.

PubMed

Eberl, Gérard

2016-08-01

The classical model of immunity posits that the immune system reacts to pathogens and injury and restores homeostasis. Indeed, a century of research has uncovered the means and mechanisms by which the immune system recognizes danger and regulates its own activity. However, this classical model does not fully explain complex phenomena, such as tolerance, allergy, the increased prevalence of inflammatory pathologies in industrialized nations and immunity to multiple infections. In this Essay, I propose a model of immunity that is based on equilibrium, in which the healthy immune system is always active and in a state of dynamic equilibrium between antagonistic types of response. This equilibrium is regulated both by the internal milieu and by the microbial environment. As a result, alteration of the internal milieu or microbial environment leads to immune disequilibrium, which determines tolerance, protective immunity and inflammatory pathology.

Unique aspects of the perinatal immune system.

PubMed

Zhang, Xiaoming; Zhivaki, Dania; Lo-Man, Richard

2017-08-01

The early stages of life are associated with increased susceptibility to infection, which is in part due to an ineffective immune system. In the context of infection, the immune system must be stimulated to provide efficient protection while avoiding insufficient or excessive activation. Yet, in early life, age-dependent immune regulation at molecular and cellular levels contributes to a reduced immunological fitness in terms of pathogen clearance and response to vaccines. To enable microbial colonization to be tolerated at birth, epigenetic immune cell programming and early life-specific immune regulatory and effector mechanisms ensure that vital functions and organ development are supported and that tissue damage is avoided. Advancement in our understanding of age-related remodelling of immune networks and the consequent tuning of immune responsiveness will open up new possibilities for immune intervention and vaccine strategies that are designed specifically for early life.

A Physical Theory of the Competition that Allows HIV to Escape from the Immune System

NASA Astrophysics Data System (ADS)

Deem, Michael

2007-03-01

Competition within the immune system may degrade immune control of viral infections. We formalize the evolution that occurs in both HIV-1 and the immune system quasispecies [1]. Inclusion of competition in the immune system leads to a novel balance between the immune response and HIV-1, in which the eventual outcome is HIV-1 escape rather than control. The analytical model reproduces the three stages of HIV-1 infection. We propose a vaccine regimen that may be able to reduce competition between T cells, potentially eliminating the third stage of HIV-1. 1) G. Wang and M. W. Deem, Phys. Rev. Lett. 97 (2006) 188106.

The Immune System in Obesity: Developing Paradigms Amidst Inconvenient Truths.

PubMed

Agrawal, Madhur; Kern, Philip A; Nikolajczyk, Barbara S

2017-08-15

Adipose tissue (AT) houses both innate and adaptive immune systems that are crucial for preserving AT function and metabolic homeostasis. In this review, we summarize recent information regarding progression of obesity-associated AT inflammation and insulin resistance. We additionally consider alterations in AT distribution and the immune system in males vs. females and among different racial populations. Innate and adaptive immune cell-derived inflammation drives insulin resistance both locally and systemically. However, new evidence also suggests that the immune system is equally vital for adipocyte differentiation and protection from ectopic lipid deposition. Furthermore, roles of anti-inflammatory immune cells such as regulatory T cells, "M2-like" macrophages, eosinophils, and mast cells are being explored, primarily due to promise of immunotherapeutic applications. Both immune responses and AT distribution are strongly influenced by factors like sex and race, which have been largely underappreciated in the field of metabolically-associated inflammation, or meta-flammation. More studies are required to recognize factors that switch inflammation from controlled to uncontrolled in obesity-associated pathogenesis and to integrate the combined effects of meta-flammation and immunometabolism. It is critical to recognize that the AT-associated immune system can be alternately beneficial and destructive; therefore, simply blocking immune responses early in obesity may not be the best clinical approach. The dearth of information on gender and race-associated disparities in metabolism, AT distribution, and the immune system suggest that a greater understanding of such differences will be critical to develop personalized treatments for obesity and the associated metabolic dysfunction.

The immune-neuro-endocrine interactions.

PubMed

Tomaszewska, D; Przekop, F

1997-06-01

This article reviews data concerning the interactions between immune, endocrine and neural systems in physiological, pathophysiological and stress conditions in animals and humans. Numerous studies have provided evidence that these systems interact with each other in maintaining homeostasis. This interaction may be classified as follows: immune, endocrine and neural cell products coexist in lymphoid, endocrine and neural tissue. Endocrine and neural mediators modulate immune system activity. Immune, endocrine and neural cells express receptors for cytokines, hormones, neuropeptides and transmitters.

The Many Roles of Galectin-3, a Multifaceted Molecule, in Innate Immune Responses against Pathogens

PubMed Central

Díaz-Alvarez, Laura

2017-01-01

Galectins are a group of evolutionarily conserved proteins with the ability to bind β-galactosides through characteristic carbohydrate-recognition domains (CRD). Galectin-3 is structurally unique among all galectins as it contains a C-terminal CRD linked to an N-terminal protein-binding domain, being the only chimeric galectin. Galectin-3 participates in many functions, both intra- and extracellularly. Among them, a prominent role for Galectin-3 in inflammation has been recognized. Galectin-3 has also been shown to directly bind to pathogens and to have various effects on the functions of the cells of the innate immune system. Thanks to these two properties, Galectin-3 participates in several ways in the innate immune response against invading pathogens. Galectin-3 has been proposed to function not only as a pattern-recognition receptor (PRR) but also as a danger-associated molecular pattern (DAMP). In this review, we analyze the various roles that have been assigned to Galectin-3, both as a PRR and as a DAMP, in the context of immune responses against pathogenic microorganisms. PMID:28607536

Drug allergy

PubMed Central

Warrington, Richard

2012-01-01

Allergic drug reactions occur when a drug, usually a low molecular weight molecule, has the ability to stimulate an immune response. This can be done in one of two ways. The first is by binding covalently to a self-protein, to produce a haptenated molecule that can be processed and presented to the adaptive immune system to induce an immune response. Sometimes the drug itself cannot do this but a reactive breakdown product of the drug is able to bind covalently to the requisite self-protein or peptide. The second way in which drugs can stimulate an immune response is by binding non-covalently to antigen presenting or antigen recognition molecules such as the major histocompatibility complex (MHC) or the T cell receptor. This is known as the p-I or pharmacological interaction hypothesis. The drug binding in this situation is reversible and stimulation of the response may occur on first exposure, not requiring previous sensitization. There is probably a dependence on the presence of certain MHC alleles and T cell receptor structures for this type of reaction to occur. PMID:22922763

Parasitism and calfhood diseases.

PubMed

Herlich, H; Douvres, F W

1977-02-01

That animals can and do acquire an effective immunity against helminth parasites has been demonstrated extensively experimentally, and the fact that domestic animals such as cattle, sheep, and horses become adults while maintaining good health in spite of constant exposure to reinfection long has suggested that immunity must be important to such survival. Although our attempts to date to vaccinate calves against helminth parasites have either failed or been unsatisfactory because of the pathosis induced by the experimental vaccines, the results are not surprising or discouraging. In contrast to the long history of immunization research on bacterial and viral diseases, only within a relatively short time have serious efforts been directed at exploiting hostal immunity for prevention and control of helminthic diseases. Unlike the comparatively simple structures of viruses and bacteria, helminths are complex multicellular animals with vast arrays of antigens and complicated physiological and immunological interactions with their hosts. Much more fundamental information on helminth-bovine interactions, on helminth antigens, and on cattle antibody systems must be developed before progress on control of cattle helminths by vaccination can be meaningful.

A close look at brain dynamics: cells and vessels seen by in vivo two-photon microscopy.

PubMed

Fumagalli, Stefano; Ortolano, Fabrizio; De Simoni, Maria-Grazia

2014-10-01

The cerebral vasculature has a unique role in providing a constant supply of oxygen and nutrients to ensure normal brain functions. Blood vessels that feed the brain are far from being simply channels for passive transportation of fluids. They form complex structures made up of different cell types. These structures regulate blood supply, local concentrations of O2 and CO2, transport of small molecules, trafficking of plasma cells and fine cerebral functions in normal and diseased brains. Until few years ago, analysis of these functions has been typically based on post mortem techniques, whose interpretation is limited by the need for tissue processing at specific times. For a reliable and effective picture of the dynamic processes in the central nervous system, real-time information in vivo is required. There are now few in vivo systems, among which two-photon microscopy (2-PM) is a truly innovative tool for studying the brain. 2-PM has been used to dissect specific aspects of vascular and immune cell dynamics in the context of neurological diseases, providing exciting results that could not have been obtained with conventional methods. This review summarizes the latest findings on vascular and immune system action in the brain, with particular focus on the dynamic responses after ischemic brain injury. 2-PM has helped define the hierarchical architecture of the brain vasculature, the dynamic interaction between the vasculature and immune cells recruited to lesion sites, the effects of blood flow on neuronal and microglial activity and the ability of cells of the neurovascular unit to regulate blood flow. Copyright © 2014 Elsevier Ltd. All rights reserved.

Validation of Procedures for Monitoring Crewmember Immune Function - Short Duration Biological Investigation

NASA Technical Reports Server (NTRS)

Sams, Clarence; Crucian, Brian; Stowe, Raymond; Pierson, Duane; Mehta, Satish; Morukov, Boris; Uchakin, Peter; Nehlsen-Cannarella, Sandra

2008-01-01

Validation of Procedures for Monitoring Crew Member Immune Function - Short Duration Biological Investigation (Integrated Immune-SDBI) will assess the clinical risks resulting from the adverse effects of space flight on the human immune system and will validate a flightcompatible immune monitoring strategy. Immune system changes will be monitored by collecting and analyzing blood, urine and saliva samples from crewmembers before, during and after space flight.

Validation of Procedures for Monitoring Crewmember Immune Function SDBI-1900, SMO-015 - Integrated Immune

NASA Technical Reports Server (NTRS)

Crucian, Brian; Stowe, Raymond; Mehta, Satish; Uchakin, Peter; Nehlsen-Cannarella, Sandra; Morukov, Boris; Pierson, Duane; Sams, Clarence

2007-01-01

There is ample evidence to suggest that space flight leads to immune system dysregulation. This may be a result of microgravity, confinement, physiological stress, radiation, environment or other mission-associated factors. The clinical risk from prolonged immune dysregulation during space flight are not yet determined, but may include increased incidence of infection, allergy, hypersensitivity, hematological malignancy or altered wound healing. Each of the clinical events resulting from immune dysfunction has the potential to impact mission critical objectives during exploration-class missions. To date, precious little in-flight immune data has been generated to assess this phenomenon. The majority of recent flight immune studies have been post-flight assessments, which may not accurately reflect the in-flight condition. There are no procedures currently in place to monitor immune function or its effect on crew health. The objective of this Supplemental Medical Objective (SMO) is to develop and validate an immune monitoring strategy consistent with operational flight requirements and constraints. This SMO will assess the clinical risks resulting from the adverse effects of space flight on the human immune system and will validate a flight-compatible immune monitoring strategy. Characterization of the clinical risk and the development of a monitoring strategy are necessary prerequisite activities prior to validating countermeasures. This study will determine, to the best level allowed by current technology, the in-flight status of crewmembers immune system. Pre-flight, in-flight and post-flight assessments of immune status, immune function, viral reactivation and physiological stress will be performed. The in-flight samples will allow a distinction between legitimate in-flight alterations and the physiological stresses of landing and readaptation which are believed to alter landing day assessments. The overall status of the immune system during flight (activation, deficiency, dysregulation) and the response of the immune system to specific latent virus reactivation (known to occur during space flight) will be thoroughly assessed. Following completion of the SMO the data will be evaluated to determine the optimal set of assays for routine monitoring of crewmember immune system function, should the clinical risk warrant such monitoring.

TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis.

PubMed

Francisco, Ngiambudulu M; Hsu, Nai-Jen; Keeton, Roanne; Randall, Philippa; Sebesho, Boipelo; Allie, Nasiema; Govender, Dhirendra; Quesniaux, Valerie; Ryffel, Bernhard; Kellaway, Lauriston; Jacobs, Muazzam

2015-06-26

Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. We generated neuron-specific TNF-deficient (NsTNF(-/-)) mice and compared outcomes of disease against TNF(f/f) control and global TNF(-/-) mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). Intracerebral M. tuberculosis infection of TNF(-/-) mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF(-/-) mice were resistant to infection and presented with a phenotype similar to that in TNF(f/f) control mice. Impaired immunity in TNF(-/-) mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB.

Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient

PubMed Central

Yanagida, Keisuke; Hla, Timothy

2017-01-01

Vertebrates are endowed with a closed circulatory system, the evolution of which required novel structural and regulatory changes. Furthermore, immune cell trafficking paradigms adapted to the barriers imposed by the closed circulatory system. How did such changes occur mechanistically? We propose that spatial compartmentalization of the lipid mediator sphingosine 1-phosphate (S1P) may be one such mechanism. In vertebrates, S1P is spatially compartmentalized in the blood and lymphatic circulation, thus comprising a sharp S1P gradient across the endothelial barrier. Circulatory S1P has critical roles in maturation and homeostasis of the vascular system as well as in immune cell trafficking. Physiological functions of S1P are tightly linked to shear stress, the key biophysical stimulus from blood flow. Thus, circulatory S1P confinement could be a primordial strategy of vertebrates in the development of a closed circulatory system. This review discusses the cellular and molecular basis of the S1P gradients and aims to interpret its physiological significance as a key feature of the closed circulatory system. PMID:27813829

Immune System and Disorders

MedlinePlus

Your immune system is a complex network of cells, tissues, and organs that work together to defend against germs. It helps ... to find and destroy them. If your immune system cannot do its job, the results can be ...

Mice with Reconstituted Human Immune System Components as a Tool to Study Immune Cell Interactions in EBV Infection.

PubMed

Heuts, Frank; Nagy, Noemi

2017-01-01

Recent developments in mouse models that harbor part of a human immune system have proved extremely valuable to study the in vivo immune response to human specific pathogens such as Epstein-Barr virus. Over the last decades, advances in immunodeficient mouse strains that can be used as recipients for human immune cells have greatly enhanced the use of these models. Here, we describe the generation of mice with reconstituted human immune system (HIS mice) using immunocompromised mice transplanted with human CD34 + hematopoietic stem cells. We will also describe how such mice, in which human immune cells are generated de novo, can be used to study EBV infection.

The cost structure of routine infant immunization services: a systematic analysis of six countries

PubMed Central

Geng, Fangli; Suharlim, Christian; Brenzel, Logan; Resch, Stephen C; Menzies, Nicolas A

2017-01-01

Abstract Little information exists on the cost structure of routine infant immunization services in low- and middle-income settings. Using a unique dataset of routine infant immunization costs from six countries, we estimated how costs were distributed across budget categories and programmatic activities, and investigated how the cost structure of immunization sites varied by country and site characteristics. The EPIC study collected data on routine infant immunization costs from 319 sites in Benin, Ghana, Honduras, Moldova, Uganda, Zambia, using a standardized approach. For each country, we estimated the economic costs of infant immunization by administrative level, budget category, and programmatic activity from a programme perspective. We used regression models to describe how costs within each category were related to site operating characteristics and efficiency level. Site-level costs (incl. vaccines) represented 77–93% of national routine infant immunization costs. Labour and vaccine costs comprised 14–69% and 13–69% of site-level cost, respectively. The majority of site-level resources were devoted to service provision (facility-based or outreach), comprising 48–78% of site-level costs across the six countries. Based on the regression analyses, sites with the highest service volume had a greater proportion of costs devoted to vaccines, with vaccine costs per dose relatively unaffected by service volume but non-vaccine costs substantially lower with higher service volume. Across all countries, more efficient sites (compared with sites with similar characteristics) had a lower cost share devoted to labour. The cost structure of immunization services varied substantially between countries and across sites within each country, and was related to site characteristics. The substantial variation observed in this sample suggests differences in operating model for otherwise similar sites, and further understanding of these differences could reveal approaches to improve efficiency and performance of immunization sites. PMID:28575193

The cost structure of routine infant immunization services: a systematic analysis of six countries.

PubMed

Geng, Fangli; Suharlim, Christian; Brenzel, Logan; Resch, Stephen C; Menzies, Nicolas A

2017-10-01

Little information exists on the cost structure of routine infant immunization services in low- and middle-income settings. Using a unique dataset of routine infant immunization costs from six countries, we estimated how costs were distributed across budget categories and programmatic activities, and investigated how the cost structure of immunization sites varied by country and site characteristics. The EPIC study collected data on routine infant immunization costs from 319 sites in Benin, Ghana, Honduras, Moldova, Uganda, Zambia, using a standardized approach. For each country, we estimated the economic costs of infant immunization by administrative level, budget category, and programmatic activity from a programme perspective. We used regression models to describe how costs within each category were related to site operating characteristics and efficiency level. Site-level costs (incl. vaccines) represented 77-93% of national routine infant immunization costs. Labour and vaccine costs comprised 14-69% and 13-69% of site-level cost, respectively. The majority of site-level resources were devoted to service provision (facility-based or outreach), comprising 48-78% of site-level costs across the six countries. Based on the regression analyses, sites with the highest service volume had a greater proportion of costs devoted to vaccines, with vaccine costs per dose relatively unaffected by service volume but non-vaccine costs substantially lower with higher service volume. Across all countries, more efficient sites (compared with sites with similar characteristics) had a lower cost share devoted to labour. The cost structure of immunization services varied substantially between countries and across sites within each country, and was related to site characteristics. The substantial variation observed in this sample suggests differences in operating model for otherwise similar sites, and further understanding of these differences could reveal approaches to improve efficiency and performance of immunization sites. © The Author 2017. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.

Neural-endocrine-immune complex in the central modulation of tumorigenesis: facts, assumptions, and hypotheses.

PubMed

Mravec, Boris; Gidron, Yori; Kukanova, Barbara; Bizik, Jozef; Kiss, Alexander; Hulin, Ivan

2006-11-01

For the precise coordination of systemic functions, the nervous system uses a variety of peripherally and centrally localized receptors, which transmit information from internal and external environments to the central nervous system. Tight interconnections between the immune, nervous, and endocrine systems provide a base for monitoring and consequent modulation of immune system functions by the brain and vice versa. The immune system plays an important role in tumorigenesis. On the basis of rich interconnections between the immune, nervous and endocrine systems, the possibility that the brain may be informed about tumorigenesis is discussed in this review article. Moreover, the eventual modulation of tumorigenesis by central nervous system is also considered. Prospective consequences of the interactions between tumor and brain for diagnosis and therapy of cancer are emphasized.

Structural Health Monitoring of Civil Infrastructure Using Optical Fiber Sensing Technology: A Comprehensive Review

PubMed Central

Ye, X. W.; Su, Y. H.; Han, J. P.

2014-01-01

In the last two decades, a significant number of innovative sensing systems based on optical fiber sensors have been exploited in the engineering community due to their inherent distinctive advantages such as small size, light weight, immunity to electromagnetic interference (EMI) and corrosion, and embedding capability. A lot of optical fiber sensor-based monitoring systems have been developed for continuous measurement and real-time assessment of diversified engineering structures such as bridges, buildings, tunnels, pipelines, wind turbines, railway infrastructure, and geotechnical structures. The purpose of this review article is devoted to presenting a summary of the basic principles of various optical fiber sensors, innovation in sensing and computational methodologies, development of novel optical fiber sensors, and the practical application status of the optical fiber sensing technology in structural health monitoring (SHM) of civil infrastructure. PMID:25133250

Structural health monitoring of civil infrastructure using optical fiber sensing technology: a comprehensive review.

PubMed

Ye, X W; Su, Y H; Han, J P

2014-01-01

In the last two decades, a significant number of innovative sensing systems based on optical fiber sensors have been exploited in the engineering community due to their inherent distinctive advantages such as small size, light weight, immunity to electromagnetic interference (EMI) and corrosion, and embedding capability. A lot of optical fiber sensor-based monitoring systems have been developed for continuous measurement and real-time assessment of diversified engineering structures such as bridges, buildings, tunnels, pipelines, wind turbines, railway infrastructure, and geotechnical structures. The purpose of this review article is devoted to presenting a summary of the basic principles of various optical fiber sensors, innovation in sensing and computational methodologies, development of novel optical fiber sensors, and the practical application status of the optical fiber sensing technology in structural health monitoring (SHM) of civil infrastructure.

Toward an understanding of immune cell sociology: real-time monitoring of cytokine secretion at the single-cell level.

PubMed

Shirasaki, Yoshitaka; Yamagishi, Mai; Shimura, Nanako; Hijikata, Atsushi; Ohara, Osamu

2013-01-01

The immune system is a very complex and dynamic cellular system, and its intricacies are considered akin to those of human society. Disturbance of homeostasis of the immune system results in various types of diseases; therefore, the homeostatic mechanism of the immune system has long been a subject of great interest in biology, and a lot of information has been accumulated at the cellular and the molecular levels. However, the sociological aspects of the immune system remain too abstract to address because of its high complexity, which mainly originates from a large number and variety of cell-cell interactions. As long-range interactions mediated by cytokines play a key role in the homeostasis of the immune system, cytokine secretion analyses, ranging from analyses of the micro level of individual cells to the macro level of a bulk of cell ensembles, provide us with a solid basis of a sociological viewpoint of the immune system. In this review, as the first step toward a comprehensive understanding of immune cell sociology, cytokine secretion of immune cells is surveyed with a special emphasis on the single-cell level, which has been overlooked but should serve as a basis of immune cell sociology. Now that it has become evident that large cell-to-cell variations in cytokine secretion exist at the single-cell level, we face a tricky yet interesting question: How is homeostasis maintained when the system is composed of intrinsically noisy agents? In this context, we discuss how the heterogeneity of cytokine secretion at the single-cell level affects our view of immune cell sociology. While the apparent inconsistency between homeostasis and cell-to-cell heterogeneity is difficult to address by a conventional reductive approach, comparison and integration of single-cell data with macroscopic data will offer us a new direction for the comprehensive understanding of immune cell sociology. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

Evaluation of immunization data completeness within a large community health care system exchanging data with a state immunization information system.

PubMed

Hendrickson, Bryan K; Panchanathan, Sarada S; Petitti, Diana

2015-01-01

Information systems are used by most states to maintain registries of immunization data both for monitoring population-level adherence and for use in clinical practice and research. Direct data exchange between such systems and electronic health record systems presents an opportunity to improve the completeness and quality of information available. Our goals were to describe and compare the completeness of the Arizona State Immunization System, the electronic health record at a large community health provider in Arizona exchanging electronic data with the Arizona system, and personal immunization records in an effort to contribute to the discussion on the completeness of state-run immunization registries and data exchange with these registries. Immunization histories from these sources were collected and reviewed sequentially. Unique dates of vaccination administrations were counted for each patient and tagged on the basis of comparisons across sources. We quantified completeness by combining information from all 3 sources and comparing each source with the complete set. We determined that the state registry was 71.8% complete, the hospital electronic health record was 81.9% complete, and personal records were 87.8% complete. Of the 2017 unique vaccination administrations, 65% were present in all 3 sources, 24.6% in 2 of the 3 sources, and 10.4% in only 1 source. Only 11% of patients had records in complete agreement across the 3 sources. This study highlights issues related to data completeness, exchange, and reporting of immunization information to state registries and suggests that there is some degree of deficiency in completeness of immunization registries and other sources. This study indicates that there is a need to strengthen links between electronic data sources with immunization information and describes potential improvements in completeness that such efforts could provide, enabling providers to better rely on state immunization registries and to improve research utilization of immunization information systems.

Continuous Dual Resetting of the Immune Repertoire as a Basic Principle of the Immune System Function.

PubMed

Balzar, Silvana

2017-01-01

Idiopathic chronic inflammatory conditions (ICIC) such as allergy, asthma, chronic obstructive pulmonary disease, and various autoimmune conditions are a worldwide health problem. Understanding the pathogenesis of ICIC is essential for their successful therapy and prevention. However, efforts are hindered by the lack of comprehensive understanding of the human immune system function. In line with those efforts, described here is a concept of stochastic continuous dual resetting (CDR) of the immune repertoire as a basic principle that governs the function of immunity. The CDR functions as a consequence of system's thermodynamically determined intrinsic tendency to acquire new states of inner equilibrium and equilibrium against the environment. Consequently, immune repertoire undergoes continuous dual (two-way) resetting: against the physiologic continuous changes of self and against the continuously changing environment. The CDR-based dynamic concept of immunity describes mechanisms of self-regulation, tolerance, and immunosenescence, and emphasizes the significance of immune system's compartmentalization in the pathogenesis of ICIC. The CDR concept's relative simplicity and concomitantly documented congruency with empirical, clinical, and experimental data suggest it may represent a plausible theoretical framework to better understand the human immune system function.

Isolation of an invertebrate-type lysozyme from the nephridia of the echiura, Urechis unicinctus, and its recombinant production and activities.

PubMed

Oh, Hye Young; Kim, Chan-Hee; Go, Hye-Jin; Park, Nam Gyu

2018-05-09

Invertebrates, unlike vertebrates which have adaptive immune system, rely heavily on the innate immune system for the defense against pathogenic bacteria. Lysozymes, along with other immune effectors, are regarded as an important group in this defense. An invertebrate-type (i-type) lysozyme, designated Urechis unicinctus invertebrate-type lysozyme, Uu-ilys, has been isolated from nephridia of Urechis unicinctus using a series of high performance liquid chromatography (HPLC), and ultrasensitive radial diffusion assay (URDA) as a bioassay system. Analyses of the primary structure and cDNA cloning revealed that Uu-ilys was approximately 14 kDa and composed of 122 amino acids (AAs) of which the precursor had a total of 160 AAs containing a signal peptide of 18 AAs and a pro-sequence of 20 AAs encoded by the nucleotide sequence of 714 bp that comprises a 5' untranslated region (UTR) of 42 bp, an open reading frame (ORF) of 483 bp, and a 3' UTR of 189 bp. Multiple sequence alignment showed Uu-ilys has high homology to i-type lysozymes from several annelids. Relatively high transcriptional expression levels of Uu-ilys was detected in nephridia, anal vesicle, and intestine. The native Uu-ilys exhibited comparable lysozyme enzymatic and antibacterial activities to hen egg white lysozyme. Collectively, these data suggest that Uu-ilys, the isolated antibacterial protein, plays a role in the immune defense mechanism of U. unicinctus. Recombinant Uu-ilys (rUu-ilys) produced in a bacterial expression system showed significantly decreased lysozyme lytic activity from that of the native while its potency on radial diffusion assay detecting antibacterial activity was retained, which may indicate the non-enzymatic antibacterial capacity of Uu-ilys. Copyright © 2018. Published by Elsevier Ltd.

Cancer exosomes and NKG2D receptor-ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance.

PubMed

Mincheva-Nilsson, Lucia; Baranov, Vladimir

2014-10-01

Human cancers constitutively produce and release endosome-derived nanometer-sized vesicles called exosomes that carry biologically active proteins, messenger and micro RNAs and serve as vehicles of intercellular communication. The tumour exosomes are present in the blood, urine and various malignant effusions such as peritoneal and pleural fluid of cancer patients and can modulate immune cells and responses thus deranging the immune system of cancer patients and giving advantage to the cancer to establish and spread itself. Here, the role of exosomes in the NKG2D receptor-ligand system's interactions is discussed. The activating NK cell receptor NKG2D and its multiple ligands, the MHC class I-related chain (MIC) A/B and the retinoic acid transcript-1/UL-16 binding proteins (RAET1/ULBP) 1-6 comprise a powerful stress-inducible danger detector system that targets infected, inflamed and malignantly transformed cells and plays a decisive role in anti-tumour immune surveillance. Mounting evidence reveals that the MIC- and RAET1/ULBP ligand family members are enriched in the endosomal compartment of various tumour cells and expressed and released into the intercellular space and bodily fluids on exosomes thus preserving their entire molecule, three-dimensional protein structure and biologic activity. The NKG2D ligand-expressing exosomes serve as decoys with a powerful ability to down regulate the cognate receptor and impair the cytotoxic function of NK-, NKT-, gamma/delta- and cytotoxic T cells. This review summarizes recent findings concerning the role of NKG2D receptor-ligand system in cancer with emphasis on regulation of NKG2D ligand expression and the immunosuppressive role of exosomally expressed NKG2D ligands. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of the protective immunogencity of the N, P, M, NV and G proteins of infectious hematopoietic necrosis virus in rainbow trout Oncorhynchus mykiss using DNA vaccines

USGS Publications Warehouse

Corbeil, S.; LaPatra, S.E.; Anderson, E.D.; Jones, J.; Vincent, B.; Hsu, Ya Li; Kurath, G.

1999-01-01

The protective immunogenicity of the nucleoprotein (N), phosphoprotein (P), matrix protein (M), non-virion protein (NV) and glycoprotein (G) of the rhabdovirus infectious hematopoietic necrosis virus (IHNV) was assessed in rainbow trout using DNA vaccine technology. DNA vaccines were produced by amplifying and cloning the viral genes in the plasmid pCDNA 3.1. The protective immunity elicited by each vaccine was evaluated through survival of immunized fry after challenge with live virus. Neutralizing antibody titers were also determined in vaccinated rainbow troutOncorhynchus mykiss fry (mean weight 2 g) and 150 g sockeye salmon Oncorhynchus nerka. The serum from the 150 g fish was also used in passive immunization studies with naïve fry. Our results showed that neither the internal structural proteins (N, P and M) nor the NV protein of IHNV induced protective immunity in fry or neutralizing antibodies in fry and 150 g fish when expressed by a DNA vaccine construct. The G protein, however, did confer significant protection in fry up to 80 d post-immunization and induced protective neutralizing antibodies. We are currently investigating the role of different arms of the fish immune system that contribute to the high level of protection against IHNV seen in vaccinated fish.

The Meninges: New Therapeutic Targets For Multiple Sclerosis

PubMed Central

Russi, Abigail E.; Brown, Melissa A.

2014-01-01

The CNS is largely comprised of non-regenerating cells, including neurons and myelin-producing oligodendrocytes, which are particularly vulnerable to immune cell mediated damage. To protect the CNS, mechanisms exist that normally restrict the transit of peripheral immune cells into the brain and spinal cord, conferring an “immune specialized” status. Thus, there has been a long-standing debate as to how these restrictions are overcome in several inflammatory diseases of the CNS, including multiple sclerosis (MS). In this review, we highlight the role of the meninges, tissues that surround and protect the CNS and enclose the cerebral spinal fluid, in promoting chronic inflammation that leads to neuronal damage. Although the meninges have traditionally been considered structures that provide physical protection for the brain and spinal cord, new data has established these tissues as sites of active immunity. It has been hypothesized that the meninges are important players in normal immunosurveillance of the CNS but also serve as initial sites of anti-myelin immune responses. The resulting robust meningeal inflammation elicits loss of localized blood barrier integrity and facilitates a large-scale influx of immune cells into the CNS parenchyma. We propose that targeting of the cells and molecules mediating these inflammatory responses within the meninges offers promising therapies for MS that are free from the constraints imposed by the blood brain barrier. Importantly, such therapies may avoid the systemic immunosuppression often associated with the existing treatments. PMID:25241937

An Automatic System of Testing the Best Stress of Installation for Semiconductor Refrigeration Piece

NASA Astrophysics Data System (ADS)

Chen, Hongyan; Song, Ping

Concerning the problems of the impact on the factors of installation about semiconductor refrigeration piece are rarely studied in China and abroad, a reasonable structure of test device is designed, using stepper motor to test the temperature of the cold surface under different stress of installation to get the best stress of installation for the semiconductor refrigeration piece. Experiments shows that the system is of good noise immunity, high controlling and measuring precision.

The immune system: a target for functional foods?

PubMed

Calder, Philip C; Kew, Samantha

2002-11-01

The immune system acts to protect the host from infectious agents that exist in the environment (bacteria, viruses, fungi, parasites) and from other noxious insults. The immune system is constantly active, acting to discriminate 'non-self' from 'self'. The immune system has two functional divisions: the innate and the acquired. Both components involve various blood-borne factors (complement, antibodies, cytokines) and cells. A number of methodologies exist to assess aspects of immune function; many of these rely upon studying cells in culture ex vivo. There are large inter-individual variations in many immune functions even among the healthy. Genetics, age, gender, smoking habits, habitual levels of exercise, alcohol consumption, diet, stage in the female menstrual cycle, stress, history of infections and vaccinations, and early life experiences are likely to be important contributors to the observed variation. While it is clear that individuals with immune responses significantly below 'normal' are more susceptible to infectious agents and exhibit increased infectious morbidity and mortality, it is not clear how the variation in immune function among healthy individuals relates to variation in susceptibility to infection. Nutrient status is an important factor contributing to immune competence: undernutrition impairs the immune system, suppressing immune functions that are fundamental to host protection. Undernutrition leading to impairment of immune function can be due to insufficient intake of energy and macronutrients and/or due to deficiencies in specific micronutrients. Often these occur in combination. Nutrients that have been demonstrated (in either animal or human studies) to be required for the immune system to function efficiently include essential amino acids, the essential fatty acid linoleic acid, vitamin A, folic acid, vitamin B6, vitamin B12, vitamin C, vitamin E, Zn, Cu, Fe and Se. Practically all forms of immunity may be affected by deficiencies in one or more of these nutrients. Animal and human studies have demonstrated that adding the deficient nutrient back to the diet can restore immune function and resistance to infection. Among the nutrients studied most in this regard are vitamin E and Zn. Increasing intakes of some nutrients above habitual and recommended levels can enhance some aspects of immune function. However, excess amounts of some nutrients also impair immune function. There is increasing evidence that probiotic bacteria improve host immune function. The effect of enhancing immune function on host resistance to infection in healthy individuals is not clear.

Design of composite microparticle systems based on pectin and waste material of propolis for modified l-alanyl-l-glutamine release and with immunostimulant activity.

PubMed

Villa Nova, Mônica; Ratti, Bianca A; Herculano, Leandro S; Bittencourt, Paulo R S; Novello, Cláudio R; Bazotte, Roberto Barbosa; Lautenschlager, Sueli de Oliveira Silva; Bruschi, Marcos Luciano

2017-12-12

Catabolic conditions like acquired immunodeficiency syndrome, cancer, and burn can cause immunosuppression. Amino acids such as alanine and glutamine are essential for the activity of the immune system. Propolis is immunostimulant and the waste of propolis extraction has been reused with technological and therapeutic purposes. Therefore, this study describes the association of propolis byproduct extract (BPE) with pectin to prepare spray-dried microparticles containing the dipeptide l-alanyl-l-glutamine as stimulant systems of neutrophils. The use of a factorial design allowed selecting the best formulation, which was characterized by morphology, size, and entrapment efficiency analyses. In addition, the systems were characterized by thermal and X-ray diffraction analysis, Fourier-transform infrared spectroscopy, in vitro drug release, and in vitro cytotoxicity and stimulation test of neutrophils. Small well-structured microparticles with good entrapment efficiency values were achieved. Thermal stability of formulation was observed, and it was proved that pectin, BPE and l-alanyl-l-glutamine were dispersed throughout the matrix. The drug was released from the microparticles during 24 h governed by swelling and diffusion. The drug-loaded formulations showed a significant stimulating effect on neutrophils. These structures could increase the activity of immune cells, and other in vitro and in vivo studies should be performed in the future.

Characterization of lipoteichoic acid structures from three probiotic Bacillus strains: involvement of D-alanine in their biological activity.

PubMed

Villéger, Romain; Saad, Naima; Grenier, Karine; Falourd, Xavier; Foucat, Loïc; Urdaci, Maria C; Bressollier, Philippe; Ouk, Tan-Sothea

2014-10-01

Probiotics represent a potential strategy to influence the host's immune system thereby modulating immune response. Lipoteichoic Acid (LTA) is a major immune-stimulating component of Gram-positive cell envelopes. This amphiphilic polymer, anchored in the cytoplasmic membrane by means of its glycolipid component, typically consists of a poly (glycerol-phosphate) chain with D-alanine and/or glycosyl substitutions. LTA is known to stimulate macrophages in vitro, leading to secretion of inflammatory mediators such as Nitric Oxide (NO). This study investigates the structure-activity relationship of purified LTA from three probiotic Bacillus strains (Bacillus cereus CH, Bacillus subtilis CU1 and Bacillus clausii O/C). LTAs were extracted from bacterial cultures and purified. Chemical modification by means of hydrolysis at pH 8.5 was performed to remove D-alanine. The molecular structure of native and modified LTAs was determined by (1)H NMR and GC-MS, and their inflammatory potential investigated by measuring NO production by RAW 264.7 macrophages. Structural analysis revealed several differences between the newly characterized LTAs, mainly relating to their D-alanylation rates and poly (glycerol-phosphate) chain length. We observed induction of NO production by LTAs from B. subtilis and B. clausii, whereas weaker NO production was observed with B. cereus. LTA dealanylation abrogated NO production independently of the glycolipid component, suggesting that immunomodulatory potential depends on D-alanine substitutions. D-alanine may control the spatial configuration of LTAs and their recognition by cell receptors. Knowledge of molecular mechanisms behind the immunomodulatory abilities of probiotics is essential to optimize their use.

Probiotic bacteria cell walls stimulate the activity of the intestinal epithelial cells and macrophage functionality.

PubMed

Lemme-Dumit, J M; Polti, M A; Perdigón, G; Galdeano, C Maldonado

2018-01-29

The effect of oral administration of probiotic bacteria cell walls (PBCWs) in the stimulation of the immune system in healthy BALB/c mice was evaluated. We focused our investigation mainly on intestinal epithelial cells (IECs) which are essential for coordinating an adequate mucosal immune response and on the functionality of macrophages. The probiotic bacteria and their cell walls were able to stimulate the IECs exhibiting an important activation and cytokine releases. Supplementation with PBCWs promoted macrophage activation from peritoneum and spleen, indicating that the PBCWs oral administration was able to improve the functionality of the macrophages. In addition, the PBCWs increased immunoglobulin A (IgA)-producing cells in the gut lamina propria in a similar way to probiotic bacteria, but this supplementation did not have an effect on the population of goblet cells in the small intestine epithelium. These results indicate that the probiotic bacteria and their cell walls have an important immunoregulatory effect on the IECs without altering the homeostatic environment but with an increase in IgA+ producing cells and in the innate immune cells, mainly those distant from the gut such as spleen and peritoneum. These findings about the capacity of the cell walls from probiotic bacteria to stimulate key cells, such as IECs and macrophages, and to improve the functioning of the immune system, suggest that those structures could be applied as a new oral adjuvant.

Addition of glycosylation to influenza A virus hemagglutinin modulates antibody-mediated recognition of H1N1 2009 pandemic viruses.

PubMed

Job, Emma R; Deng, Yi-Mo; Barfod, Kenneth K; Tate, Michelle D; Caldwell, Natalie; Reddiex, Scott; Maurer-Stroh, Sebastian; Brooks, Andrew G; Reading, Patrick C

2013-03-01

Seasonal influenza A viruses (IAV) originate from pandemic IAV and have undergone changes in antigenic structure, including addition of glycans to the viral hemagglutinin (HA). Glycans on the head of HA promote virus survival by shielding antigenic sites, but highly glycosylated seasonal IAV are inactivated by soluble lectins of the innate immune system. In 2009, human strains of pandemic H1N1 [A(H1N1)pdm] expressed a single glycosylation site (Asn(104)) on the head of HA. Since then, variants with additional glycosylation sites have been detected, and the location of these sites has been distinct to those of recent seasonal H1N1 strains. We have compared wild-type and reverse-engineered A(H1N1)pdm IAV with differing potential glycosylation sites on HA for sensitivity to collectins and to neutralizing Abs. Addition of a glycan (Asn(136)) to A(H1N1)pdm HA was associated with resistance to neutralizing Abs but did not increase sensitivity to collectins. Moreover, variants expressing Asn(136) showed enhanced growth in A(H1N1)pdm-vaccinated mice, consistent with evasion of Ab-mediated immunity in vivo. Thus, a fine balance exists regarding the optimal pattern of HA glycosylation to facilitate evasion of Ab-mediated immunity while maintaining resistance to lectin-mediated defenses of the innate immune system.

Dynamical properties of a tumor growth system in the presence of immunization and colored cross-correlated noises

NASA Astrophysics Data System (ADS)

Jia, Zheng-Lin; Mei, Dong-Cheng

2010-05-01

We investigate the effects of the noise parameters and immunization strength β on the dynamical properties of a tumor growth system with both immunization and colored cross-correlated noises. The analytical expressions for the associated relaxation time TC and the normalized correlation function C(s) are derived by means of the projection operator method. The results indicate that: (i) TC as a function of the multiplicative noise intensity α shows resonance-like behavior, i.e. the curves of TC versus α exhibit a single-peak structure and its peak position changes with increasing correlation strength between noises λ, the autocorrelation time of multiplicative noise τ1, the autocorrelation time of additive noise τ2 and the cross-correlation time τ3. This behavior can be understood in terms of the noise-enhanced stability effect and the influence of the memory effects on it. (ii) The increasing λ, τ1, τ2 and the additive noise intensity D slow down the fluctuation decay of the tumor population, whereas the increasing τ3 and β speed it up. (iii) C(s) increases as λ, τ1, τ2 and β increase, while it decreases with τ3 increasing. Our study shows that the effects of some noise parameters on tumor growth can be modified due to the presence of the immunization effect.

Recognition of LPS by TLR4: Potential for Anti-Inflammatory Therapies

PubMed Central

Nijland, Reindert; Hofland, Tom; van Strijp, Jos A. G.

2014-01-01

LPS molecules of marine bacteria show structures distinct from terrestrial bacteria, due to the different environment that marine bacteria live in. Because of these different structures, lipid A molecules from marine bacteria are most often poor stimulators of the Toll-like receptor 4 (TLR4) pathway. Due to their low stimulatory potential, these lipid A molecules are suggested to be applicable as antagonists of TLR4 signaling in sepsis patients, where this immune response is amplified and unregulated. Antagonizing lipid A molecules might be used for future therapies against sepsis, therapies that currently do not exist. In this review, we will discuss these differences in lipid A structures and their recognition by the immune system. The modifications present in marine lipid A structures are described, and their potential as LPS antagonists will be discussed. Finally, since clinical trials built on antagonizing lipid A molecules have proven unsuccessful, we propose to also focus on different aspects of the TLR4 signaling pathway when searching for new potential drugs. Furthermore, we put forward the notion that bacteria probably already produce inhibitors of TLR4 signaling, making these bacterial products interesting molecules to investigate for future sepsis therapies. PMID:25056632

Structural Basis of Semaphorin-Plexin Recognition and Viral Mimicry from Sema7A and A39R Complexes with PlexinC1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Heli; Juo, Z. Sean; Shim, Ann Hye-Ryong

Repulsive signaling by Semaphorins and Plexins is crucial for the development and homeostasis of the nervous, immune, and cardiovascular systems. Sema7A acts as both an immune and a neural Semaphorin through PlexinC1, and A39R is a Sema7A mimic secreted by smallpox virus. We report the structures of Sema7A and A39R complexed with the Semaphorin-binding module of PlexinC1. Both structures show two PlexinC1 molecules symmetrically bridged by Semaphorin dimers, in which the Semaphorin and PlexinC1 {beta} propellers interact in an edge-on, orthogonal orientation. Both binding interfaces are dominated by the insertion of the Semaphorin's 4c-4d loop into a deep groove inmore » blade 3 of the PlexinC1 propeller. A39R appears to achieve Sema7A mimicry by preserving key Plexin-binding determinants seen in the mammalian Sema7A complex that have evolved to achieve higher affinity binding to the host-derived PlexinC1. The complex structures support a conserved Semaphorin-Plexin recognition mode and suggest that Plexins are activated by dimerization.« less

Immunology for physicists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perelson, A.S.; Weisbuch, G.

1997-10-01

The immune system is a complex system of cells and molecules that can provide us with a basic defense against pathogenic organisms. Like the nervous system, the immune system performs pattern recognition tasks, learns, and retains a memory of the antigens that it has fought. The immune system contains more than 10{sup 7} different clones of cells that communicate via cell-cell contact and the secretion of molecules. Performing complex tasks such as learning and memory involves cooperation among large numbers of components of the immune system and hence there is interest in using methods and concepts from statistical physics. Furthermore,more » the immune response develops in time and the description of its time evolution is an interesting problem in dynamical systems. In this paper, the authors provide a brief introduction to the biology of the immune system and discuss a number of immunological problems in which the use of physical concepts and mathematical methods has increased our understanding. {copyright} {ital 1997} {ital The American Physical Society}« less

Simulations of centriole of polarized centrosome as a monopole antenna in immune and viral synapses.

PubMed

Dvorak, Josef; Melichar, Bohuslav; Filipova, Alzbeta; Grimova, Jana; Grimova, Nela; Rozsypalova, Aneta; Buka, David; Voboril, Rene; Zapletal, Radek; Buchler, Tomas; Richter, Igor; Buka, David

2018-01-01

The immune synapse (IS) is a temporary interface between an antigen-presenting cell and an effector lymphocyte. Viral synapse is a molecularly organized cellular junction that is structurally similar to the IS. Primary cilium is considered as a functional homologue of the IS due to the morphological and functional similarities in architecture between both micotubule structures. It has been hypothesized that endogenous electromagnetic field in the cell is generated by a unique cooperating system between mitochondria and microtubules. We are extending this prior hypothesis of the endogenous electromagnetic field in the cell postulating that polarized centriole in immune and viral synapse could serve as a monopole antenna. This is an addition to our hypothesis that primary cilium could serve as a monopole antenna. We simulated the distribution of electric field of centriole of polarized centrosome as a monopole antenna in immune and viral synapse. Very weak electromagnetic field of polarized centriole of CD8+ T lymphocyte in IS can contribute to the transport of cytolytic granules into the attacked (cancer) cell. Analogically, very weak electromagnetic field of polarized centriole in viral synapse of infected CD4 cells can aid the transport of viruses (human immunodeficiency virus) to non-infected CD4 cells. We hypothesized that healthy organisms need these monopole antennas. If, during the neoplastic transformation, healthy cells lose monopole antennas in form of primary cilia, the IS aims to replace them by monopole antennas of polarized centrioles in IS to restore homeostasis.

Septic Arthritis

MedlinePlus

... Weak immune system. People with a weak immune system are at greater risk of septic arthritis. This includes people with diabetes, kidney and liver problems, and those taking drugs that suppress their immune systems. Joint trauma. Animal bites, puncture woods or cuts ...

[Regulatory role of the immune system in the organism].

PubMed

Alekseev, L P; Khaitov, R M

2010-08-01

The paper presents modern idea of regulatory role of the human immune system in performing a number of physiological functions including intercellular interactions, reproductive process, and forming of protection against external and internal aggression. Significance of the immune system is considered and substantiated, that of genes of the human immune response in particular in provision of human survival as a biological species.

Integrated Immune

NASA Technical Reports Server (NTRS)

Crucian, Brian; Mehta, Satish; Stowe, Raymond; Uchakin, Peter; Quiriarte, Heather; Pierson, Duane; Sams, Clarnece

2010-01-01

This slide presentation reviews the program to replace several recent studies about astronaut immune systems with one comprehensive study that will include in-flight sampling. The study will address lack of in-flight data to determine the inflight status of immune systems, physiological stress, viral immunity, to determine the clinical risk related to immune dysregulation for exploration class spaceflight, and to determine the appropriate monitoring strategy for spaceflight-associated immune dysfunction, that could be used for the evaluation of countermeasures.

Trained immunity in newborn infants of HBV-infected mothers

PubMed Central

Hong, Michelle; Sandalova, Elena; Low, Diana; Gehring, Adam J.; Fieni, Stefania; Amadei, Barbara; Urbani, Simonetta; Chong, Yap-Seng; Guccione, Ernesto; Bertoletti, Antonio

2015-01-01

The newborn immune system is characterized by an impaired Th1-associated immune response. Hepatitis B virus (HBV) transmitted from infected mothers to newborns is thought to exploit the newborns’ immune system immaturity by inducing a state of immune tolerance that facilitates HBV persistence. Contrary to this hypothesis, we demonstrate here that HBV exposure in utero triggers a state of trained immunity, characterized by innate immune cell maturation and Th1 development, which in turn enhances the ability of cord blood immune cells to respond to bacterial infection in vitro. These training effects are associated with an alteration of the cytokine environment characterized by low IL-10 and, in most cases, high IL-12p40 and IFN-α2. Our data uncover a potentially symbiotic relationship between HBV and its natural host, and highlight the plasticity of the fetal immune system following viral exposure in utero. PMID:25807344

The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC.

PubMed

Frantz, Stefan; Falcao-Pires, Ines; Balligand, Jean-Luc; Bauersachs, Johann; Brutsaert, Dirk; Ciccarelli, Michele; Dawson, Dana; de Windt, Leon J; Giacca, Mauro; Hamdani, Nazha; Hilfiker-Kleiner, Denise; Hirsch, Emilio; Leite-Moreira, Adelino; Mayr, Manuel; Thum, Thomas; Tocchetti, Carlo G; van der Velden, Jolanda; Varricchi, Gilda; Heymans, Stephane

2018-03-01

Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies. © 2018 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

The mucosal immune system: From dentistry to vaccine development

PubMed Central

KIYONO, Hiroshi; AZEGAMI, Tatsuhiko

2015-01-01

The oral cavity is the beginning of the aero-digestive tract, which is covered by mucosal epithelium continuously under the threat of invasion of pathogens, it is thus protected by the mucosal immune system. In the early phase of our scientific efforts for the demonstration of mucosal immune system, dental science was one of major driving forces due to their foreseeability to use oral immunity for the control of oral diseases. The mucosal immune system is divided functionally into, but interconnected inductive and effector sites. Intestinal Peyer’s patches (PPs) are an inductive site containing antigen-sampling M cells and immunocompetent cells required to initiate antigen-specific immune responses. At effector sites, PP-originated antigen-specific IgA B cells become plasma cells to produce polymeric IgA and form secretory IgA by binding to poly-Ig receptor expressed on epithelial cells for protective immunity. The development of new-generation mucosal vaccines, including the rice-based oral vaccine MucoRice, on the basis of the coordinated mucosal immune system is a promising strategy for the control of mucosal infectious diseases. PMID:26460320

Activation of the immune system by bacterial CpG-DNA

PubMed Central

Häcker, Georg; Redecke, Vanessa; Häcker, Hans

2002-01-01

The past decade has seen a remarkable process of refocusing in immunology. Cells of the innate immune system, especially macrophages and dendritic cells, have been at the centre of this process. These cells had been regarded by some scientists as non-specific, sometimes perhaps even confined to the menial job of serving T cells by scavenging antigen and presenting it to the sophisticated adaptive immune system. Only over the last few years has it become unequivocally clear that cells of the innate immunity hold, by variation of context and mode of antigen presentation, the power of shaping an adaptive immune response. The innate immune response, in turn, is to a significant degree the result of stimulation by so-called pathogen-associated molecular patterns (PAMPs). One compound with high stimulatory potential for the innate immune system is bacterial DNA. Here we will review recent evidence that bacterial DNA should be ranked with other PAMPs such as lipopolysaccharide (LPS) and lipoteichoic acid. We will further review our present knowledge of DNA recognition and DNA-dependent signal transduction in cells of the immune system. PMID:11918685

Comparative genomic analyses reveal a vast, novel network of nucleotide-centric systems in biological conflicts, immunity and signaling

PubMed Central

Burroughs, A. Maxwell; Zhang, Dapeng; Schäffer, Daniel E.; Iyer, Lakshminarayan M.; Aravind, L.

2015-01-01

Cyclic di- and linear oligo-nucleotide signals activate defenses against invasive nucleic acids in animal immunity; however, their evolutionary antecedents are poorly understood. Using comparative genomics, sequence and structure analysis, we uncovered a vast network of systems defined by conserved prokaryotic gene-neighborhoods, which encode enzymes generating such nucleotides or alternatively processing them to yield potential signaling molecules. The nucleotide-generating enzymes include several clades of the DNA-polymerase β-like superfamily (including Vibrio cholerae DncV), a minimal version of the CRISPR polymerase and DisA-like cyclic-di-AMP synthetases. Nucleotide-binding/processing domains include TIR domains and members of a superfamily prototyped by Smf/DprA proteins and base (cytokinin)-releasing LOG enzymes. They are combined in conserved gene-neighborhoods with genes for a plethora of protein superfamilies, which we predict to function as nucleotide-sensors and effectors targeting nucleic acids, proteins or membranes (pore-forming agents). These systems are sometimes combined with other biological conflict-systems such as restriction-modification and CRISPR/Cas. Interestingly, several are coupled in mutually exclusive neighborhoods with either a prokaryotic ubiquitin-system or a HORMA domain-PCH2-like AAA+ ATPase dyad. The latter are potential precursors of equivalent proteins in eukaryotic chromosome dynamics. Further, components from these nucleotide-centric systems have been utilized in several other systems including a novel diversity-generating system with a reverse transcriptase. We also found the Smf/DprA/LOG domain from these systems to be recruited as a predicted nucleotide-binding domain in eukaryotic TRPM channels. These findings point to evolutionary and mechanistic links, which bring together CRISPR/Cas, animal interferon-induced immunity, and several other systems that combine nucleic-acid-sensing and nucleotide-dependent signaling. PMID:26590262

T cell receptor cross-reactivity directed by antigen-dependent tuning of peptide-MHC molecular flexibility

PubMed Central

Borbulevych, Oleg Y.; Piepenbrink, Kurt H.; Gloor, Brian E.; Scott, Daniel R.; Sommese, Ruth F.; Cole, David K.; Sewell, Andrew K.; Baker, Brian M.

2011-01-01

Summary Tell mediated immunity requires T cell receptor (TCR) cross-reactivity, the mechanisms behind which remain incompletely elucidated. The αβ TCR A6 recognizes both the Tax (LLFGYPVYV) and Tel1p (MLWGYLQYV) peptides presented by the human class I MHC molecule HLA-A2. Here we found that although the two ligands are ideal structural mimics, they form substantially different interfaces with A6, with conformational differences in the peptide, the TCR, and unexpectedly, the MHC molecule. The differences between the Tax and Tel1p ternary complexes could not be predicted from the free peptide-MHC structures and are inconsistent with a traditional induced-fit mechanism. Instead, the differences were attributable to peptide and MHC molecular motion present in Tel1p-HLA-A2 but absent in Tax-HLA-A2. Differential “tuning” of the dynamic properties of HLA-A2 by the Tax and Tel1p peptides thus facilitates cross-recognition and impacts how structural diversity can be presented to and accommodated by receptors of the immune system. PMID:20064447

Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody

PubMed Central

Kwong, Peter D.; Wyatt, Richard; Robinson, James; Sweet, Raymond W.; Sodroski, Joseph; Hendrickson, Wayne A.

2017-01-01

The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. These interactions initiate a fusion of the viral and cellular membranes. Although gpl20 can elicit virus-neutralizing antibodies, HIV eludes the immune system. We have solved the X-ray crystal structure at 2.5 Å resolution of an HIV-1 gp120 core complexed with a two-domain fragment of human CD4 and an antigen-binding fragment of a neutralizing antibody that blocks chemokine-receptor binding. The structure reveals a cavity-laden CD4-gp120 interface, a conserved binding site for the chemokine receptor, evidence for a conformational change upon CD4 binding, the nature of a CD4-induced antibody epitope, and specific mechanisms for immune evasion. Our results provide a framework for understanding the complex biology of HIV entry into cells and should guide efforts to intervene. PMID:9641677

Promoting tissue regeneration by modulating the immune system.

PubMed

Julier, Ziad; Park, Anthony J; Briquez, Priscilla S; Martino, Mikaël M

2017-04-15

The immune system plays a central role in tissue repair and regeneration. Indeed, the immune response to tissue injury is crucial in determining the speed and the outcome of the healing process, including the extent of scarring and the restoration of organ function. Therefore, controlling immune components via biomaterials and drug delivery systems is becoming an attractive approach in regenerative medicine, since therapies based on stem cells and growth factors have not yet proven to be broadly effective in the clinic. To integrate the immune system into regenerative strategies, one of the first challenges is to understand the precise functions of the different immune components during the tissue healing process. While remarkable progress has been made, the immune mechanisms involved are still elusive, and there is indication for both negative and positive roles depending on the tissue type or organ and life stage. It is well recognized that the innate immune response comprising danger signals, neutrophils and macrophages modulates tissue healing. In addition, it is becoming evident that the adaptive immune response, in particular T cell subset activities, plays a critical role. In this review, we first present an overview of the basic immune mechanisms involved in tissue repair and regeneration. Then, we highlight various approaches based on biomaterials and drug delivery systems that aim at modulating these mechanisms to limit fibrosis and promote regeneration. We propose that the next generation of regenerative therapies may evolve from typical biomaterial-, stem cell-, or growth factor-centric approaches to an immune-centric approach. Most regenerative strategies have not yet proven to be safe or reasonably efficient in the clinic. In addition to stem cells and growth factors, the immune system plays a crucial role in the tissue healing process. Here, we propose that controlling the immune-mediated mechanisms of tissue repair and regeneration may support existing regenerative strategies or could be an alternative to using stem cells and growth factors. The first part of this review we highlight key immune mechanisms involved in the tissue healing process and marks them as potential target for designing regenerative strategies. In the second part, we discuss various approaches using biomaterials and drug delivery systems that aim at modulating the components of the immune system to promote tissue regeneration. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Debunking the Myth of Exercise-Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan.

PubMed

Campbell, John P; Turner, James E

2018-01-01

Epidemiological evidence indicates that regular physical activity and/or frequent structured exercise reduces the incidence of many chronic diseases in older age, including communicable diseases such as viral and bacterial infections, as well as non-communicable diseases such as cancer and chronic inflammatory disorders. Despite the apparent health benefits achieved by leading an active lifestyle, which imply that regular physical activity and frequent exercise enhance immune competency and regulation, the effect of a single bout of exercise on immune function remains a controversial topic. Indeed, to this day, it is perceived by many that a vigorous bout of exercise can temporarily suppress immune function. In the first part of this review, we deconstruct the key pillars which lay the foundation to this theory-referred to as the "open window" hypothesis-and highlight that: (i) limited reliable evidence exists to support the claim that vigorous exercise heightens risk of opportunistic infections; (ii) purported changes to mucosal immunity, namely salivary IgA levels, after exercise do not signpost a period of immune suppression; and (iii) the dramatic reductions to lymphocyte numbers and function 1-2 h after exercise reflects a transient and time-dependent redistribution of immune cells to peripheral tissues, resulting in a heightened state of immune surveillance and immune regulation, as opposed to immune suppression. In the second part of this review, we provide evidence that frequent exercise enhances-rather than suppresses-immune competency, and highlight key findings from human vaccination studies which show heightened responses to bacterial and viral antigens following bouts of exercise. Finally, in the third part of this review, we highlight that regular physical activity and frequent exercise might limit or delay aging of the immune system, providing further evidence that exercise is beneficial for immunological health. In summary, the over-arching aim of this review is to rebalance opinion over the perceived relationships between exercise and immune function. We emphasize that it is a misconception to label any form of acute exercise as immunosuppressive, and, instead, exercise most likely improves immune competency across the lifespan.

Learning and Memory... and the Immune System

ERIC Educational Resources Information Center

Marin, Ioana; Kipnis, Jonathan

2013-01-01

The nervous system and the immune system are two main regulators of homeostasis in the body. Communication between them ensures normal functioning of the organism. Immune cells and molecules are required for sculpting the circuitry and determining the activity of the nervous system. Within the parenchyma of the central nervous system (CNS),…

IgY: a promising antibody for use in immunodiagnostic and in immunotherapy.

PubMed

Dias da Silva, Wilmar; Tambourgi, Denise V

2010-06-15

Immunoglobulin IgY is the major antibody produced by chickens (Gallus domesticus). After their V-C gene is rearranged in B cells, IgY is continually synthesized, excreted into the blood and transferred to the egg yolk, where it is accumulated. IgY is produced by hens to provide their offspring with an effective humoral immunity against the commonest avian pathogens until full maturation of their own immune system. In this review we aim to give an overview about the generation, structure, properties of IgY, as well as the advantages of chicken antibodies use over mammalian antibodies in immunodiagnostics and immunotherapy. Copyright 2010 Elsevier B.V. All rights reserved.

Serine protease inhibitors of parasitic helminths.

PubMed

Molehin, Adebayo J; Gobert, Geoffrey N; McManus, Donald P

2012-05-01

Serine protease inhibitors (serpins) are a superfamily of structurally conserved proteins that inhibit serine proteases and play key physiological roles in numerous biological systems such as blood coagulation, complement activation and inflammation. A number of serpins have now been identified in parasitic helminths with putative involvement in immune regulation and in parasite survival through interference with the host immune response. This review describes the serpins and smapins (small serine protease inhibitors) that have been identified in Ascaris spp., Brugia malayi, Ancylostoma caninum Onchocerca volvulus, Haemonchus contortus, Trichinella spiralis, Trichostrongylus vitrinus, Anisakis simplex, Trichuris suis, Schistosoma spp., Clonorchis sinensis, Paragonimus westermani and Echinococcus spp. and discusses their possible biological functions, including roles in host-parasite interplay and their evolutionary relationships.

Hevein-Like Antimicrobial Peptides of Plants.

PubMed

Slavokhotova, A A; Shelenkov, A A; Andreev, Ya A; Odintsova, T I

2017-12-01

Plant antimicrobial peptides represent one of the evolutionarily oldest innate immunity components providing the first line of host defense to pathogen attacks. This review is dedicated to a small, currently actively studied family of hevein-like peptides that can be found in various monocot and dicot plants. The review thoroughly describes all known peptides belonging to this family including data on their structures, functions, and antimicrobial activity. The main features allowing to assign these peptides to a separate family are given, and the specific characteristics of each peptide are described. Further, the mode of action for hevein-like peptides, their role in plant immune system, and the applications of these molecules in biotechnology and medicine are considered.

Tissue homeostasis and immunity--more on models.

PubMed

Cunliffe, J

2006-09-01

This article continues the ongoing debate around models of the immune system. Earlier contributors have paid much attention to the various processes that lead to adaptive immune system aggression or tolerance. They have often based their discussions around facts that have been established by experimental investigation. However, both the observation and interpretation of these facts have been influenced by the function--or system goal--that is believed to have generated them. The perception of this function (of all or part of the immune system) is influenced by long established theories in immunology (e.g. horror autotoxicus, clonal deletion in utero, pathogen elimination, clonal selection, auto-immunity and so on) which, for many, have become enshrined as facts. One function that has had less consideration and has not been extensively investigated is the maintenance of tissue homeostasis. When the immune system is viewed from this perspective, the facts invite alternative interpretations. Whilst this perspective may not necessarily be the only valid one, let alone a correct one, viewing things this way--at least briefly--might help to expose hidden assumptions. It also emphasizes that the immune system is a system and, as such, it can by analysed through the principles of general systems theory.

Prolonged protection against Intranasal challenge with influenza virus following systemic immunization or combinations of mucosal and systemic immunizations with a heat-labile toxin mutant.

PubMed

Zhou, Fengmin; Goodsell, Amanda; Uematsu, Yasushi; Vajdy, Michael

2009-04-01

Seasonal influenza virus infections cause considerable morbidity and mortality in the world, and there is a serious threat of a pandemic influenza with the potential to cause millions of deaths. Therefore, practical influenza vaccines and vaccination strategies that can confer protection against intranasal infection with influenza viruses are needed. In this study, we demonstrate that using LTK63, a nontoxic mutant of the heat-labile toxin from Escherichia coli, as an adjuvant for both mucosal and systemic immunizations, systemic (intramuscular) immunization or combinations of mucosal (intranasal) and intramuscular immunizations protected mice against intranasal challenge with a lethal dose of live influenza virus at 3.5 months after the second immunization.

The S(c)ensory Immune System Theory.

PubMed

Veiga-Fernandes, Henrique; Freitas, António A

2017-10-01

Viewpoints on the immune system have evolved across different paradigms, including the clonal selection theory, the idiotypic network, and the danger and tolerance models. Herein, we propose that in multicellular organisms, where panoplies of cells from different germ layers interact and immune cells are constantly generated, the behavior of the immune system is defined by the rules governing cell survival, systems physiology and organismic homeostasis. Initially, these rules were imprinted at the single cell-protist level, but supervened modifications in the transition to multicellular organisms. This context determined the emergence of the 'sensory immune system', which operates in a s(c)ensor mode to ensure systems physiology, organismic homeostasis, and perpetuation of its replicating molecules. Copyright © 2017 Elsevier Ltd. All rights reserved.

Novel vaccine development strategies for inducing mucosal immunity

PubMed Central

Fujkuyama, Yoshiko; Tokuhara, Daisuke; Kataoka, Kosuke; Gilbert, Rebekah S; McGhee, Jerry R; Yuki, Yoshikazu; Kiyono, Hiroshi; Fujihashi, Kohtaro

2012-01-01

To develop protective immune responses against mucosal pathogens, the delivery route and adjuvants for vaccination are important. The host, however, strives to maintain mucosal homeostasis by responding to mucosal antigens with tolerance, instead of immune activation. Thus, induction of mucosal immunity through vaccination is a rather difficult task, and potent mucosal adjuvants, vectors or other special delivery systems are often used, especially in the elderly. By taking advantage of the common mucosal immune system, the targeting of mucosal dendritic cells and microfold epithelial cells may facilitate the induction of effective mucosal immunity. Thus, novel routes of immunization and antigen delivery systems also show great potential for the development of effective and safe mucosal vaccines against various pathogens. The purpose of this review is to introduce several recent approaches to induce mucosal immunity to vaccines, with an emphasis on mucosal tissue targeting, new immunization routes and delivery systems. Defining the mechanisms of mucosal vaccines is as important as their efficacy and safety, and in this article, examples of recent approaches, which will likely accelerate progress in mucosal vaccine development, are discussed. PMID:22380827

Host Immune Response to Influenza A Virus Infection.

PubMed

Chen, Xiaoyong; Liu, Shasha; Goraya, Mohsan Ullah; Maarouf, Mohamed; Huang, Shile; Chen, Ji-Long

2018-01-01

Influenza A viruses (IAVs) are contagious pathogens responsible for severe respiratory infection in humans and animals worldwide. Upon detection of IAV infection, host immune system aims to defend against and clear the viral infection. Innate immune system is comprised of physical barriers (mucus and collectins), various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, which provide first line of defense against IAV infection. The adaptive immunity is mediated by B cells and T cells, characterized with antigen-specific memory cells, capturing and neutralizing the pathogen. The humoral immune response functions through hemagglutinin-specific circulating antibodies to neutralize IAV. In addition, antibodies can bind to the surface of infected cells and induce antibody-dependent cell-mediated cytotoxicity or complement activation. Although there are neutralizing antibodies against the virus, cellular immunity also plays a crucial role in the fight against IAVs. On the other hand, IAVs have developed multiple strategies to escape from host immune surveillance for successful replication. In this review, we discuss how immune system, especially innate immune system and critical molecules are involved in the antiviral defense against IAVs. In addition, we highlight how IAVs antagonize different immune responses to achieve a successful infection.

Tiling solutions for optimal biological sensing

NASA Astrophysics Data System (ADS)

Walczak, Aleksandra M.

2015-10-01

Biological systems, from cells to organisms, must respond to the ever-changing environment in order to survive and function. This is not a simple task given the often random nature of the signals they receive, as well as the intrinsically stochastic, many-body and often self-organized nature of the processes that control their sensing and response and limited resources. Despite a wide range of scales and functions that can be observed in the living world, some common principles that govern the behavior of biological systems emerge. Here I review two examples of very different biological problems: information transmission in gene regulatory networks and diversity of adaptive immune receptor repertoires that protect us from pathogens. I discuss the trade-offs that physical laws impose on these systems and show that the optimal designs of both immune repertoires and gene regulatory networks display similar discrete tiling structures. These solutions rely on locally non-overlapping placements of the responding elements (genes and receptors) that, overall, cover space nearly uniformly.

The immune signaling pathways of Manduca sexta

PubMed Central

Cao, Xiaolong; He, Yan; Hu, Yingxia; Wang, Yang; Chen, Yun-Ru; Bryant, Bart; Clem, Rollie J.; Schwartz, Lawrence M.; Blissard, Gary; Jiang, Haobo

2015-01-01

Signal transduction pathways and their coordination are critically important for proper functioning of animal immune systems. Our knowledge of the constituents of the intracellular signaling network in insects mainly comes from genetic analyses in Drosophila melanogaster. To facilitate future studies of similar systems in the tobacco hornworm and other lepidopteran insects, we have identified and examined the homologous genes in the genome of Manduca sexta. Based on 1:1 orthologous relationships in most cases, we hypothesize that the Toll, Imd, MAPK-JNK-p38 and JAK-STAT pathways are intact and operative in this species, as are most of the regulatory mechanisms. Similarly, cellular processes such as autophagy, apoptosis and RNA interference probably function in similar ways, because their mediators and modulators are mostly conserved in this lepidopteran species. We have annotated a total of 186 genes encoding 199 proteins, studied their domain structures and evolution, and examined their mRNA levels in tissues at different life stages. Such information provides a genomic perspective of the intricate signaling system in a non-drosophiline insect. PMID:25858029

A Comparative Study of Human Saposins.

PubMed

Garrido-Arandia, María; Cuevas-Zuviría, Bruno; Díaz-Perales, Araceli; Pacios, Luis F

2018-02-14

Saposins are small proteins implicated in trafficking and loading of lipids onto Cluster of Differentiation 1 (CD1) receptor proteins that in turn present lipid antigens to T cells and a variety of T-cell receptors, thus playing a crucial role in innate and adaptive immune responses in humans. Despite their low sequence identity, the four types of human saposins share a similar folding pattern consisting of four helices linked by three conserved disulfide bridges. However, their lipid-binding abilities as well as their activities in extracting, transporting and loading onto CD1 molecules a variety of sphingo- and phospholipids in biological membranes display two striking characteristics: a strong pH-dependence and a structural change between a compact, closed conformation and an open conformation. In this work, we present a comparative computational study of structural, electrostatic, and dynamic features of human saposins based upon their available experimental structures. By means of structural alignments, surface analyses, calculation of pH-dependent protonation states, Poisson-Boltzmann electrostatic potentials, and molecular dynamics simulations at three pH values representative of biological media where saposins fulfill their function, our results shed light into their intrinsic features. The similarities and differences in this class of proteins depend on tiny variations of local structural details that allow saposins to be key players in triggering responses in the human immune system.

Structural basis for complement evasion by Lyme disease pathogen Borrelia burgdorferi.

PubMed

Bhattacharjee, Arnab; Oeemig, Jesper S; Kolodziejczyk, Robert; Meri, Taru; Kajander, Tommi; Lehtinen, Markus J; Iwaï, Hideo; Jokiranta, T Sakari; Goldman, Adrian

2013-06-28

Borrelia burgdorferi spirochetes that cause Lyme borreliosis survive for a long time in human serum because they successfully evade the complement system, an important arm of innate immunity. The outer surface protein E (OspE) of B. burgdorferi is needed for this because it recruits complement regulator factor H (FH) onto the bacterial surface to evade complement-mediated cell lysis. To understand this process at the molecular level, we used a structural approach. First, we solved the solution structure of OspE by NMR, revealing a fold that has not been seen before in proteins involved in complement regulation. Next, we solved the x-ray structure of the complex between OspE and the FH C-terminal domains 19 and 20 (FH19-20) at 2.83 Å resolution. The structure shows that OspE binds FH19-20 in a way similar to, but not identical with, that used by endothelial cells to bind FH via glycosaminoglycans. The observed interaction of OspE with FH19-20 allows the full function of FH in down-regulation of complement activation on the bacteria. This reveals the molecular basis for how B. burgdorferi evades innate immunity and suggests how OspE could be used as a potential vaccine antigen.

A benign helminth alters the host immune system and the gut microbiota in a rat model system.

PubMed

Wegener Parfrey, Laura; Jirků, Milan; Šíma, Radek; Jalovecká, Marie; Sak, Bohumil; Grigore, Karina; Jirků Pomajbíková, Kateřina

2017-01-01

Helminths and bacteria are major players in the mammalian gut ecosystem and each influences the host immune system and health. Declines in helminth prevalence and bacterial diversity appear to play a role in the dramatic rise of immune mediated inflammatory diseases (IMIDs) in western populations. Helminths are potent modulators of immune system and their reintroduction is a promising therapeutic avenue for IMIDs. However, the introduction of helminths represents a disturbance for the host and it is important to understand the impact of helminth reintroduction on the host, including the immune system and gut microbiome. We tested the impact of a benign tapeworm, Hymenolepis diminuta, in a rat model system. We find that H. diminuta infection results in increased interleukin 10 gene expression in the beginning of the prepatent period, consistent with induction of a type 2 immune response. We also find induction of humoral immunity during the patent period, shown here by increased IgA in feces. Further, we see an immuno-modulatory effect in the small intestine and spleen in patent period, as measured by reductions in tissue immune cells. We observed shifts in microbiota community composition during the patent period (beta-diversity) in response to H. diminuta infection. However, these compositional changes appear to be minor; they occur within families and genera common to both treatment groups. There was no change in alpha diversity. Hymenolepis diminuta is a promising model for helminth therapy because it establishes long-term, stable colonization in rats and modulates the immune system without causing bacterial dysbiosis. These results suggest that the goal of engineering a therapeutic helminth that can safely manipulate the mammalian immune system without disrupting the rest of the gut ecosystem is in reach.

A benign helminth alters the host immune system and the gut microbiota in a rat model system

PubMed Central

Wegener Parfrey, Laura; Jirků, Milan; Šíma, Radek; Jalovecká, Marie; Sak, Bohumil; Grigore, Karina; Jirků Pomajbíková, Kateřina

2017-01-01

Helminths and bacteria are major players in the mammalian gut ecosystem and each influences the host immune system and health. Declines in helminth prevalence and bacterial diversity appear to play a role in the dramatic rise of immune mediated inflammatory diseases (IMIDs) in western populations. Helminths are potent modulators of immune system and their reintroduction is a promising therapeutic avenue for IMIDs. However, the introduction of helminths represents a disturbance for the host and it is important to understand the impact of helminth reintroduction on the host, including the immune system and gut microbiome. We tested the impact of a benign tapeworm, Hymenolepis diminuta, in a rat model system. We find that H. diminuta infection results in increased interleukin 10 gene expression in the beginning of the prepatent period, consistent with induction of a type 2 immune response. We also find induction of humoral immunity during the patent period, shown here by increased IgA in feces. Further, we see an immuno-modulatory effect in the small intestine and spleen in patent period, as measured by reductions in tissue immune cells. We observed shifts in microbiota community composition during the patent period (beta-diversity) in response to H. diminuta infection. However, these compositional changes appear to be minor; they occur within families and genera common to both treatment groups. There was no change in alpha diversity. Hymenolepis diminuta is a promising model for helminth therapy because it establishes long-term, stable colonization in rats and modulates the immune system without causing bacterial dysbiosis. These results suggest that the goal of engineering a therapeutic helminth that can safely manipulate the mammalian immune system without disrupting the rest of the gut ecosystem is in reach. PMID:28771620

Improving vaccine registries through mobile technologies: a vision for mobile enhanced Immunization information systems.

PubMed

Wilson, Kumanan; Atkinson, Katherine M; Deeks, Shelley L; Crowcroft, Natasha S

2016-01-01

Immunization registries or information systems are critical to improving the quality and evaluating the ongoing success of immunization programs. However, the completeness of these systems is challenged by a myriad of factors including the fragmentation of vaccine administration, increasing mobility of individuals, new vaccine development, use of multiple products, and increasingly frequent changes in recommendations. Mobile technologies could offer a solution, which mitigates some of these challenges. Engaging individuals to have more control of their own immunization information using their mobile devices could improve the timeliness and accuracy of data in central immunization information systems. Other opportunities presented by mobile technologies that could be exploited to improve immunization information systems include mobile reporting of adverse events following immunization, the capacity to scan 2D barcodes, and enabling bidirectional communication between individuals and public health officials. Challenges to utilizing mobile solutions include ensuring privacy of data, access, and equity concerns, obtaining consent and ensuring adoption of technology at sufficiently high rates. By empowering individuals with their own health information, mobile technologies can also serve as a mechanism to transfer immunization information as individuals cross local, regional, and national borders. Ultimately, mobile enhanced immunization information systems can help realize the goal of the individual, the healthcare provider, and public health officials always having access to the same immunization information. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Osteoimmunology and Beyond

PubMed Central

Ginaldi, Lia; De Martinis, Massimo

2016-01-01

Abstract: Objective Osteoimmunology investigates interactions between skeleton and immune system. In the light of recent discoveries in this field, a new reading register of osteoporosis is actually emerging, in which bone and immune cells are strictly interconnected. Osteoporosis could therefore be considered a chronic immune mediated disease which shares with other age related disorders a common inflammatory background. Here, we highlight these recent discoveries and the new landscape that is emerging. Method Extensive literature search in PubMed central. Results While the inflammatory nature of osteoporosis has been clearly recognized, other interesting aspects of osteoimmunology are currently emerging. In addition, mounting evidence indicates that the immunoskeletal interface is involved in the regulation of important body functions beyond bone remodeling. Bone cells take part with cells of the immune system in various immunological functions, configuring a real expanded immune system, and are therefore variously involved not only as target but also as main actors in various pathological conditions affecting primarily the immune system, such as autoimmunity and immune deficiencies, as well as in aging, menopause and other diseases sharing an inflammatory background. Conclusion The review highlights the complexity of interwoven pathways and shared mechanisms of the crosstalk between the immune and bone systems. More interestingly, the interdisciplinary field of osteoimmunology is now expanding beyond bone and immune cells, defining new homeostatic networks in which other organs and systems are functionally interconnected. Therefore, the correct skeletal integrity maintenance may be also relevant to other functions outside its involvement in bone mineral homeostasis, hemopoiesis and immunity. PMID:27604089

Immunotoxicological effects of JP-8 jet fuel exposure.

PubMed

Harris, D T; Sakiestewa, D; Robledo, R F; Witten, M

1997-01-01

Chronic exposure to jet fuel has been shown to have adverse effects on human liver function, to cause emotional dysfunction, to cause abnormal electroencephalograms, to cause shortened attention spans, and to decrease sensorimotor speed (3-5). Due to the decision by the United States Air Force to implement the widespread use of JP-8 jet fuel in its operations, a thorough understanding of its potential effects upon exposed personnel is both critical and necessary. Exposure to potential environmental toxicants such as JP-8 may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.); e.g., the immune system. Significant changes in immune consequences, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long-lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed for 1h/day for 7 days to varying concentrations of aerosolized JP-8 jet fuel to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on their immune systems. It was observed that even at exposure concentrations as low as 100 mg/m3 detrimental effects on the immune system occurred. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in losses of different immune cell subpopulations depending upon the immune organ being examined. Further, JP-8 exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low concentration exposure of mice to JP-8 jet fuel caused significant toxicological effects on the immune system. It appears that the immune system may be the most sensitive indicator of toxicological damage due to JP-8 exposure, as effects were seen at concentrations of jet fuel that did not evidence change in other biological systems. Such changes may have significant effects on the health of the exposed individual.

Immune mediators in the brain and peripheral tissues in autism spectrum disorder

PubMed Central

Estes, Myka L.; McAllister, A. Kimberley

2017-01-01

Increasing evidence points to a central role for immune dysregulation in autism spectrum disorder (ASD). Several ASD risk genes encode components of the immune system and many maternal immune system-related risk factors — including autoimmunity, infection and fetal reactive antibodies — are associated with ASD. In addition, there is evidence of ongoing immune dysregulation in individuals with ASD and animal models of this disorder. Recently, several molecular signalling pathways have been identified that link immune activation to ASD phenotypes, including pathways downstream of cytokines, hepatocyte growth factor receptor (MET), MHCI molecules, microglia and complement factors. These findings indicate that the immune system is a point of convergence for various ASD-related genetic and environmental risk factors. PMID:26189694

Modernizing Immunization Practice Through the Use of Cloud Based Platforms.

PubMed

Bell, Cameron; Atkinson, Katherine M; Wilson, Kumanan

2017-04-01

Collection of timely and accurate immunization information is essential for effective immunization programs. Current immunization information systems have important limitations that impact the ability to collect this data. Based on our experience releasing a national immunization app we describe a cloud-based platform that would allow individuals to store their records digitally and exchange these records with public health information systems thus improving the quality of immunization information held by individuals and public health officials.

Breast Milk and Solid Food Shaping Intestinal Immunity

PubMed Central

Parigi, Sara M.; Eldh, Maria; Larssen, Pia; Gabrielsson, Susanne; Villablanca, Eduardo J.

2015-01-01

After birth, the intestinal immune system enters a critical developmental stage, in which tolerogenic and pro-inflammatory cells emerge to contribute to the overall health of the host. The neonatal health is continuously challenged by microbial colonization and food intake, first in the form of breast milk or formula and later in the form of solid food. The microbiota and dietary compounds shape the newborn immune system, which acquires the ability to induce tolerance against innocuous antigens or induce pro-inflammatory immune responses against pathogens. Disruption of these homeostatic mechanisms might lead to undesired immune reactions, such as food allergies and inflammatory bowel disease. Hence, a proper education and maturation of the intestinal immune system is likely important to maintain life-long intestinal homeostasis. In this review, the most recent literature regarding the effects of dietary compounds in the development of the intestinal immune system are discussed. PMID:26347740

Selfish brain and selfish immune system interplay: A theoretical framework for metabolic comorbidities of mood disorders.

PubMed

Yamagata, Ana Sayuri; Mansur, Rodrigo Barbachan; Rizzo, Lucas Bortolotto; Rosenstock, Tatiana; McIntyre, Roger S; Brietzke, Elisa

2017-01-01

According to the "selfish brain" theory, the brain regulates its own energy supply influencing the peripheral metabolism and food intake according to its needs. The immune system has been likewise "selfish" due to independent energy consumption; and it may compete with the brain (another high energy-consumer) for glucose. In mood disorders, stress in mood episodes or physiological stress activate homeostasis mechanisms from the brain and the immune system to solve the imbalance. The interaction between the selfish brain and the selfish immune system may explain various conditions of medical impairment in mood disorders, such as Metabolic Syndrome (MetS), obesity, type 2 diabetes mellitus (T2DM) and immune dysregulation. The objective of this study is to comprehensively review the literature regarding the competition between the brain and the immune system for energy substrate. Targeting the energetic regulation of the brain and the immune system and their cross-talk open alternative treatments and a different approach in the study of general medical comorbidities in mood disorders, although more investigation is needed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Acute and Subacute Oral Toxicity of Periodate in Rats

DTIC Science & Technology

2014-11-17

presence of decreased TSH, a pattern associated with uremia. Sodium periodate exposed rats exhibited both activation of the innate immune system and...associated with kidney disease are characterized by activation of the innate immune system coupled with immune deficiency. Sodium periodate exposed rats...exhibited both activation of the innate immune system and lymphocyte depletion; however, the pattern of effects was more indicative of a stress leukogram

Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity

NASA Astrophysics Data System (ADS)

van de Pavert, Serge A.; Ferreira, Manuela; Domingues, Rita G.; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F.; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O'Toole, Tom; Mizee, Mark R.; Habani, Yasmin; Haak, Esther; Santori, Fabio R.; Littman, Dan R.; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J. Pedro; Mebius, Reina E.; Veiga-Fernandes, Henrique

2014-04-01

The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity.

PubMed

van de Pavert, Serge A; Ferreira, Manuela; Domingues, Rita G; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O'Toole, Tom; Mizee, Mark R; Habani, Yasmin; Haak, Esther; Santori, Fabio R; Littman, Dan R; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J Pedro; Mebius, Reina E; Veiga-Fernandes, Henrique

2014-04-03

The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.