WorldWideScience

Sample records for adaptive immune inflammation

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

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

    2016-01-01

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

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

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

    2016-01-01

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

  3. Adaptive immunity alters distinct host feeding pathways during nematode induced inflammation, a novel mechanism in parasite expulsion.

    John J Worthington

    2013-01-01

    Full Text Available Gastrointestinal infection is often associated with hypophagia and weight loss; however, the precise mechanisms governing these responses remain poorly defined. Furthermore, the possibility that alterations in feeding during infection may be beneficial to the host requires further study. We used the nematode Trichinella spiralis, which transiently inhabits the small intestine before migrating to skeletal muscle, as a biphasic model of infection to determine the cellular and molecular pathways controlling feeding during enteric and peripheral inflammation. Through the infection of genetically modified mice lacking cholecystokinin, Tumor necrosis factor α receptors and T and B-cells, we observed a biphasic hypophagic response to infection resulting from two separate immune-driven mechanisms. The enteroendocrine I-cell derived hormone cholecystokinin is an essential mediator of initial hypophagia and is induced by CD4+ T-cells during enteritis. In contrast, the second hypophagic response is extra-intestinal and due to the anorectic effects of TNFα during peripheral infection of the muscle. Moreover, via maintaining naive levels of the adipose secreted hormone leptin throughout infection we demonstrate a novel feedback loop in the immunoendocrine axis. Immune driven I-cell hyperplasia and resultant weight loss leads to a reduction in the inflammatory adipokine leptin, which in turn heightens protective immunity during infection. These results characterize specific immune mediated mechanisms which reduce feeding during intestinal or peripheral inflammation. Importantly, the molecular mediators of each phase are entirely separate. The data also introduce the first evidence that I-cell hyperplasia is an adaptively driven immune response that directly impinges on the outcome to infection.

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

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

    2016-01-01

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

  5. Origins of adaptive immunity.

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

    2011-01-01

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

  6. Sterile inflammation induced by Carbopol elicits robust adaptive immune responses in the absence of pathogen-associated molecular patterns

    Gartlan, Kate H.; Krashias, George; Wegmann, Frank; Hillson, William R.; Scherer, Erin M.; Greenberg, Philip D.; Eisenbarth, Stephanie C.; Moghaddam, Amin E.; Sattentau, Quentin J.

    2016-01-01

    Carbopol is a polyanionic carbomer used in man for topical application and drug delivery purposes. However parenteral administration of Carbopol in animal models results in systemic adjuvant activity including strong pro-inflammatory type-1 T-cell (Th1) polarization. Here we investigated potential pathways of immune activation by Carbopol by comparison with other well-characterized adjuvants. Carbopol administration triggered rapid and robust leukocyte recruitment, pro-inflammatory cytokine secretion and antigen capture largely by inflammatory monocytes. The induction of antigen specific Th1 cells by Carbopol was found to occur via a non-canonical pathway, independent of MyD88/TRIF signaling and in the absence of pattern-recognition-receptor (PRR) activation typically associated with Th1/Ig2a induction. Using multispectral fluorescence imaging (Imagestream) and electron microscopy we demonstrated that phagocytic uptake of Carbopol particles followed by entry into the phagosomal/lysosomal pathway elicited conformational changes to the polymer and reactive oxygen species (ROS) production. We therefore conclude that Carbopol may mediate its adjuvant activity via novel mechanisms of antigen presenting cell activation and Th1 induction, leading to enhanced IgG2a responses independent of microbial pattern recognition. PMID:27005810

  7. Inflammation, immunity, and vaccines for Helicobacter pylori infection.

    Velin, Dominique; Straubinger, Kathrin; Gerhard, Markus

    2016-09-01

    The tight control of the innate and adaptive immune responses in the stomach mucosa during chronic Helicobacter pylori infection is of prime importance for the bacteria to persist and for the host to prevent inflammation-driven diseases. This review summarizes recent data on the roles of innate and adaptive immune responses during H. pylori/host interactions. In addition, the latest preclinical developments of H. pylori vaccines are discussed with a special focus on the clinical trial reported by Zeng et al., who provided evidence that oral vaccination significantly reduces the acquisition of natural H. pylori infection in children. PMID:27531535

  8. Brucella evasion of adaptive immunity.

    Martirosyan, Anna; Gorvel, Jean-Pierre

    2013-02-01

    The complex immune system of mammals is the result of evolutionary forces that include battles against pathogens, as sensing and defeating intruders is a prerequisite to host survival. On the other hand, microorganisms have evolved multiple mechanisms to evade both arms of immunity: the innate and the adaptive immune systems. The successful pathogenic intracellular bacterium Brucella is not an exception to the rule: Brucella displays mechanisms that allow evasion of immune surveillance in order to establish persistent infections in mammals. In this review, we highlight some key mechanisms that pathogenic Brucella use to evade the adaptive immune system. PMID:23374122

  9. Inflammation and Immune Response in COPD: Where Do We Stand?

    Nikoletta Rovina

    2013-01-01

    Full Text Available Increasing evidence indicates that chronic inflammatory and immune responses play key roles in the development and progression of COPD. Recent data provide evidence for a role in the NLRP3 inflammasome in the airway inflammation observed in COPD. Cigarette smoke activates innate immune cells by triggering pattern recognition receptors (PRRs to release “danger signal”. These signals act as ligands to Toll-like receptors (TLRs, triggering the production of cytokines and inducing innate inflammation. In smokers who develop COPD there appears to be a specific pattern of inflammation in the airways and parenchyma as a result of both innate and adaptive immune responses, with the predominance of CD8+ and CD4+ cells, and in the more severe disease, with the presence of lymphoid follicles containing B lymphocytes and T cells. Furthermore, viral and bacterial infections interfere with the chronic inflammation seen in stable COPD and exacerbations via pathogen-associated molecular patterns (PAMPs. Finally, autoimmunity is another novel aspect that may play a critical role in the pathogenesis of COPD. This review is un update of the currently discussed roles of inflammatory and immune responses in the pathogenesis of COPD.

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

    Hepworth, Matthew R.; Sonnenberg, Gregory F.

    2014-01-01

    Innate lymphoid cells (ILCs) are a group of lymphocytes that promote rapid cytokine-dependent innate immunity, inflammation and tissue repair. In addition, a growing body of evidence suggests ILCs can influence adaptive immune cell responses. During fetal development a subset of ILCs orchestrate the generation and maturation of secondary lymphoid tissues. Following birth, ILCs continue to modulate adaptive immune cell responses indirectly through interactions with stromal cells in lymphoid ti...

  11. IMMUNOLOGICAL PROCESSES IN CANCER: A LINK BETWEEN INFLAMMATION AND IMMUNITY

    Vanessa Jacob Victorino

    2014-01-01

    Full Text Available Cancer is a worldwide issue and one of the most relevant death causes in child and adults. There are several causes that can lead to cancer development. It is well known that inflammation is one known hallmark of cancer and it favors tumor cells growth. Several alterations in immunological and inflammatory processes are caused in response to tumor presence and both innate and adaptive immunity have effective mechanism to destroy tumor cells. Nevertheless, distinct tumor types developed mechanisms to evade anti-tumor immunological responses. Here, we revise researches regarding inflammation and immune response during cancer development, as well as cancer signaling pathways and immunotherapy that have been performed in Brazil. The better understanding of the mechanisms regarding cancer and immunological processes is of huge importance and it may support the development of new cancer targets.

  12. Microbial Induction of Immunity, Inflammation And Cancer

    StephenJohnO'Keefe

    2011-01-01

    Full Text Available The human microbiota presents a highly active metabolic that influences the state of health of our gastrointestinal tracts as well as our susceptibility to disease. Although much of our initial microbiota is adopted from our mothers, its final composition and diversity is determined by environmental factors. Westernization has significantly altered our microbial function. Extensive experimental and clinical evidence indicates that the westernized diet, rich in animal products and low in complex carbohydrates, plus the overuse of antibiotics and underuse of breastfeeding, leads to a heightened inflammatory potential of the microbiota. Chronic inflammation leads to the expression of certain diseases in genetically predisposed individuals. Antibiotics and a ‘clean’ environment, termed the ‘hygiene hypothesis’, has been linked to the rise in allergy and inflammatory bowel disease, due to impaired beneficial bacterial exposure and education of the gut immune system, which comprises the largest immune organ within the body. The elevated risk of colon cancer is associated with the suppression of microbial fermentation and butyrate production, as butyrate provides fuel for the mucosa and is anti-inflammatory and anti-proliferative. This article will summarize the work to date highlighting the complicated and dynamic relationship between the gut microbiota and immunity, inflammation and carcinogenesis.

  13. Microbial induction of immunity, inflammation, and cancer.

    Greer, Julia B; O'Keefe, Stephen John

    2011-01-01

    The human microbiota presents a highly active metabolic that influences the state of health of our gastrointestinal tracts as well as our susceptibility to disease. Although much of our initial microbiota is adopted from our mothers, its final composition and diversity is determined by environmental factors. Westernization has significantly altered our microbial function. Extensive experimental and clinical evidence indicates that the westernized diet, rich in animal products and low in complex carbohydrates, plus the overuse of antibiotics and underuse of breastfeeding, leads to a heightened inflammatory potential of the microbiota. Chronic inflammation leads to the expression of certain diseases in genetically predisposed individuals. Antibiotics and a "clean" environment, termed the "hygiene hypothesis," has been linked to the rise in allergy and inflammatory bowel disease, due to impaired beneficial bacterial exposure and education of the gut immune system, which comprises the largest immune organ within the body. The elevated risk of colon cancer is associated with the suppression of microbial fermentation and butyrate production, as butyrate provides fuel for the mucosa and is anti-inflammatory and anti-proliferative. This article will summarize the work to date highlighting the complicated and dynamic relationship between the gut microbiota and immunity, inflammation and carcinogenesis. PMID:21423403

  14. Aging, inflammation, immunity and periodontal disease.

    Ebersole, Jeffrey L; Graves, Christina L; Gonzalez, Octavio A; Dawson, Dolph; Morford, Lorri A; Huja, Pinar Emecen; Hartsfield, James K; Huja, Sarandeep S; Pandruvada, Subramanya; Wallet, Shannon M

    2016-10-01

    The increased prevalence and severity of periodontal disease have long been associated with aging, such that this oral condition affects the majority of the adult population over 50 years of age. Although the immune system is a critical component for maintaining health, aging can be characterized by quantitative and qualitative modifications of the immune system. This process, termed 'immunosenescence', is a progressive modification of the immune system that leads to greater susceptibility to infections, neoplasia and autoimmunity, presumably reflecting the prolonged antigenic stimulation and/or stress responses that occur across the lifespan. Interestingly, the global reduction in the host capability to respond effectively to these challenges is coupled with a progressive increase in the general proinflammatory status, termed 'inflammaging'. Consistent with the definition of immunosenescence, it has been suggested that the cumulative effect of prolonged exposure of the periodontium to microbial challenge is, at least in part, a contributor to the effects of aging on these tissues. Thus, it has also been hypothesized that alterations in the function of resident immune and nonimmune cells of the periodontium contribute to the expression of inflammaging in periodontal disease. Although the majority of aging research has focused on the adaptive immune response, it is becoming increasingly clear that the innate immune compartment is also highly affected by aging. Thus, the phenomenon of immunosenescence and inflammaging, expressed as age-associated changes within the periodontium, needs to be more fully understood in this era of precision and personalized medicine and dentistry. PMID:27501491

  15. Alternative adaptive immunity in invertebrates

    Kurtz, Joachim; Armitage, Sophie Alice Octavia

    2006-01-01

    Vertebrate adaptive immunity is characterized by challenge-specific long-term protection. This specific memory is achieved through the vast diversity of somatically rearranged immunological receptors such as antibodies. Whether or not invertebrates are capable of a comparable phenotypic plasticit...... and memory has long been a matter of debate. A recent study on Anopheles gambiae mosquitoes now establishes Down syndrome cell adhesion molecule (Dscam) as a key immune surveillance factor with characteristics analogous to antibodies....

  16. Inflammation, Immunity, and Vaccines for Helicobacter pylori Infection

    Walduck, Anna; Andersen, Leif P; Raghavan, Sukanya

    2015-01-01

    During the last year, a variety of studies have been published that increases our understanding of the basic mechanisms of immunity and inflammation in Helicobacter pylori infection and progression to gastric cancer. Innate immune regulation and epithelial cell response were covered by several...... year that reveal detailed insight into immunity and regulation of inflammation, the contribution of immune cells to the development of gastric cancer, and understanding mechanisms of vaccine-induced protection....

  17. Innate and adaptive immunity in inflammatory bowel disease

    Britta Siegmund; Martin Zeitz

    2011-01-01

    Inflammatory bowel diseases are the consequence of a dysregulated mucosal immune system. The mucosal immune system consists of two arms, innate and adaptive immunity, that have been studied separately for a long time. Functional studies from in vivo models of intestinal inflammation as well as results from genome-wide association studies strongly suggest a cross-regulation of both arms. The present review will illustrate this interaction by selecting examples from innate immunity and adaptive immunity, and their direct impact on each other. Broadening our view by focusing on the cross-regulated areas of the mucosal immune system will not only facilitate our understanding of disease, but furthermore will allow identification of future therapeutic targets.

  18. Innate and adaptive immunity in inflammatory bowel disease

    BrittaSiegmund; MartinZeitz

    2011-01-01

    Inflammatory bowel diseases are the consequence of a dysregulated mucosal immune system. The mucosal immune system consists of two arms, innate and adaptive immunity, that have been studied separately for a long time. Functional studies from in vivo models of intestinal inflammation as well as results from genome-wide association studies strongly suggest a crossregulation of both arms. The present review will illustrate this interaction by selecting examples from innate immunity and adaptive immunity, and their direct impact on each other. Broadening our view by focusing on the cross-regulated areas of the mucosal immune system will not only facilitate our understanding of disease, but furthermore will allow identification of future therapeutic targets.

  19. Blurring Borders: Innate Immunity with Adaptive Features

    K. Kvell

    2007-01-01

    Full Text Available Adaptive immunity has often been considered the penultimate of immune capacities. That system is now being deconstructed to encompass less stringent rules that govern its initiation, actual effector activity, and ambivalent results. Expanding the repertoire of innate immunity found in all invertebrates has greatly facilitated the relaxation of convictions concerning what actually constitutes innate and adaptive immunity. Two animal models, incidentally not on the line of chordate evolution (C. elegans and Drosophila, have contributed enormously to defining homology. The characteristics of specificity and memory and whether the antigen is pathogenic or nonpathogenic reveal considerable information on homology, thus deconstructing the more fundamentalist view. Senescence, cancer, and immunosuppression often associated with mammals that possess both innate and adaptive immunity also exist in invertebrates that only possess innate immunity. Strict definitions become blurred casting skepticism on the utility of creating rigid definitions of what innate and adaptive immunity are without considering overlaps.

  20. Gastrointestinal inflammation and associated immune activation in schizophrenia

    Severance, Emily G.; Alaedini, Armin; Yang, Shuojia; Halling, Meredith; Gressitt, Kristin L.; Stallings, Cassie R.; Origoni, Andrea E.; Vaughan, Crystal; Khushalani, Sunil; Leweke, F. Markus; Dickerson, Faith B.; Yolken, Robert H.

    2012-01-01

    Immune factors are implicated in normal brain development and in brain disorder pathogenesis. Pathogen infection and food antigen penetration across gastrointestinal barriers are means by which environmental factors might affect immune-related neurodevelopment. Here, we test if gastrointestinal inflammation is associated with schizophrenia and therefore, might contribute to bloodstream entry of potentially neurotropic milk and gluten exorphins and/or immune activation by food antigens. IgG an...

  1. Bioactive lipids as modulators of immunity, inflammation and emotions.

    Chiurchiù, Valerio; Maccarrone, Mauro

    2016-08-01

    Lipids are not only constituents of cellular membranes but also key signaling mediators, thus acting as 'bioactive lipids'. Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation and maintenance of homeostasis. Accumulated evidence indicates the existence of a bidirectional relationship between immune and nervous systems, whereby inflammatory mediators can directly modulate emotions that, in turn, can strongly influence immune responses, thus affecting health. This review summarizes current knowledge on the ability of several families of bioactive lipids to regulate immunity and inflammation (through pro-inflammatory or anti-inflammatory effects), as well as to control emotions and mood-related manifestations, advocating these substances as an attractive interface between 'mind' and 'body', and as a potential target to treat inflammatory/immune-mediated mood disorders. PMID:27372887

  2. Effects of recombinant bovine somatotropin during the periparturient period on innate and adaptive immune responses, systemic inflammation, and metabolism of dairy cows.

    Silva, P R B; Machado, K S; Da Silva, D N Lobão; Moraes, J G N; Keisler, D H; Chebel, R C

    2015-07-01

    The aim of this experiment was to determine effects of treating peripartum dairy cows with body condition score ≥3.75 with recombinant bovine somatotropin (rbST) on immune, inflammatory, and metabolic responses. Holstein cows (253±1d of gestation) were assigned randomly to 1 of 3 treatments: untreated control (n=53), rbST87.5 (n=56; 87.5mg of rbST), and rbST125 (n=57; 125mg of rbST). Cows in the rbST87.5 and rbST125 treatments received rbST weekly from -21 to 28d relative to calving. Growth hormone, insulin-like growth factor 1, haptoglobin, tumor necrosis factor α, nonesterified fatty acids, β-hydroxybutyrate, glucose, and cortisol concentrations were determined weekly from -21 to 21d relative to calving. Blood sampled weekly from -14 to 21d relative to calving was used for hemogram and polymorphonuclear leukocyte (PMNL) expression of adhesion molecules, phagocytosis, and oxidative burst. Cows were vaccinated with ovalbumin at -21, -7, and 7d relative to calving, and blood was collected weekly from -21 to 21d relative to calving to determine IgG anti-ovalbumin concentrations. A subsample of cows had liver biopsied -21, -7, and 7d relative to calving to determine total lipids, triglycerides, and glycogen content. Growth hormone concentrations prepartum (control=11.0±1.2, rbST87.5=14.1±1.2, rbST125=15.1±1.3ng/mL) and postpartum (control=14.4±1.1, rbST87.5=17.8±1.2, rbST125=21.8±1.1ng/mL) were highest for rbST125 cows. Cows treated with rbST had higher insulin-like growth factor 1 concentrations than control cows (control=110.5±4.5, rbST87.5=126.2±4.5, rbST125=127.2±4.5ng/mL) only prepartum. Intensity of L-selectin expression was higher for rbST125 than for control and rbST87.5 cows [control=3,590±270, rbST87.5=3,279±271, rbST125=4,371±279 geometric mean fluorescence intensity (GMFI)] in the prepartum period. The PMNL intensities of phagocytosis (control=3,131±130, rbST87.5=3,391±133, rbST125=3,673±137 GMFI) and oxidative burst (control=9,588±746

  3. The origins of vertebrate adaptive immunity

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

    2010-01-01

    Adaptive immunity is mediated through numerous genetic and cellular processes that generate favourable somatic variants of antigen-binding receptors under evolutionary selection pressure by pathogens and other factors. Advances in our understanding of immunity in mammals and other model organisms are revealing the underlying basis and complexity of this remarkable system. Although the evolution of adaptive immunity has been considered to occur by acquisition of novel molecular capabilities, a...

  4. The unfolded protein response in immunity and inflammation.

    Grootjans, Joep; Kaser, Arthur; Kaufman, Randal J; Blumberg, Richard S

    2016-08-01

    The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses. PMID:27346803

  5. Heme on innate immunity and inflammation

    Dutra, Fabianno F.; Bozza, Marcelo T.

    2014-01-01

    Heme is an essential molecule expressed ubiquitously all through our tissues. Heme plays major functions in cellular physiology and metabolism as the prosthetic group of diverse proteins. Once released from cells and from hemeproteins free heme causes oxidative damage and inflammation, thus acting as a prototypic damage-associated molecular pattern. In this context, free heme is a critical component of the pathological process of sterile and infectious hemolytic conditions including malaria, ...

  6. Inflammation, immunity, and vaccines for Helicobacter

    Aebischer, Toni; Meyer, Thomas F; Andersen, Leif P

    2010-01-01

    host immune system. The hope is that by deciphering the deterministic rules--if any--of this interplay, we will eventually be able to predict, treat, and ultimately prevent disease. Over the past year, research on the immunology of this infection started to probe the role of small noncoding RNAs, a......Helicobacter pylori represents the major etiologic agent of gastritis, gastric, and duodenal ulcer disease and can cause gastric cancer and mucosa-associated lymphoid tissue B-cell lymphoma. It is clear that the consequences of infection reflect diverse outcomes of the interaction of bacteria and...... novel class of immune response regulators. Furthermore, we learned new details on how infection is detected by innate pattern recognition receptors. Induction of effective cell-mediated immunity will be key for the development of a vaccine, and new work published analyzed the relevance and contribution...

  7. Inflammation and Immune System Alterations in Frailty

    Yao, Xu; Li, Huifen; Leng, Sean X.

    2011-01-01

    Frailty is an important geriatric syndrome characterized by multi-system dysregulation. Substantial evidence suggests heightened inflammatory state and significant immune system alterations in frailty. A heightened inflammatory state is marked by increases in levels of inflammatory molecules (IL-6 and CRP) and counts of white blood cell and its subpopulations, which may play an important role in the pathogenesis of frailty, directly or through its detrimental influence to other physiologic sy...

  8. Regulation of T cell immunity in atopic dermatitis by microbes: The Yin and Yang of cutaneous inflammation

    Tilo eBiedermann

    2015-07-01

    Full Text Available Atopic dermatitis (AD is a chronic inflammatory skin disease predominantly mediated by T helper cells. While numerous adaptive immune mechanisms in AD pathophysiology have been elucidated in detail, deciphering the impact of innate immunity in AD pathogenesis has made substantial progress in recent years and is currently a fast evolving field. As innate and adaptive immunity are intimately linked cross-talks between these two branches of the immune system are critically influencing the resulting immune response and disease. Innate immune recognition of the cutaneous microbiota was identified to substantially contribute to immune homeostasis and shaping of protective adaptive immunity in the absence of inflammation. Disturbances in the composition of the skin microbiome with reduced microbial diversity and overabundance of Staphylococcus spp. have been shown to be associated with AD inflammation. Distinct S. aureus associated microbial associated molecular patterns (MAMPs binding to TLR2 heterodimers could be identified to initiate long lasting cutaneous inflammation driven by T helper cells and consecutively local immune suppression by induction of myeloid derived suppressor cells (MDSC further favoring secondary skin infections as often seen in AD patients. Moreover dissecting cellular and molecular mechanisms in cutaneous innate immune sensing in AD pathogenesis paved the way for exploiting regulatory and anti-inflammatory pathways to attenuate skin inflammation. Activation of the innate immune system by MAMPs of non-pathogenic bacteria on AD skin alleviated cutaneous inflammation. The induction of tolerogenic dendritic cells, Interleukin-10 expression and regulatory Tr1 cells were shown to mediate this beneficial effect. Thus, activation of innate immunity by MAMPs of non-pathogenic bacteria for induction of regulatory T cell phenotypes seems to be a promising strategy for treatment of inflammatory skin disorders as atopic dermatitis. These

  9. Inflammation, immune activation, and cardiovascular disease in HIV.

    Nou, Eric; Lo, Janet; Grinspoon, Steven K

    2016-06-19

    Cardiovascular disease is one of the leading causes of morbidity and mortality in people living with HIV. Several epidemiological studies have shown an increased risk of myocardial infarction and stroke compared to uninfected controls. Although traditional risk factors contribute to this increased risk of cardiovascular disease, HIV-specific mechanisms likely also play a role. Systemic inflammation has been linked to cardiovascular disease in several populations suffering from chronic inflammation, including people living with HIV. Although antiretroviral therapy reduces immune activation, levels of inflammatory markers remain elevated compared to uninfected controls. The causes of this sustained immune response are likely multifactorial and incompletely understood. In this review, we summarize the evidence describing the relationship between inflammation and cardiovascular disease and discuss potential anti-inflammatory treatment options for cardiometabolic disease in people living with HIV. PMID:27058351

  10. Role of glutathione in immunity and inflammation in the lung

    Pietro Ghezzi

    2011-01-01

    Full Text Available Pietro GhezziBrighton and Sussex Medical School, Trafford Centre, Falmer, Brighton, UKAbstract: Reactive oxygen species and thiol antioxidants, including glutathione (GSH, regulate innate immunity at various levels. This review outlines the redox-sensitive steps of the cellular mechanisms implicated in inflammation and host defense against infection, and describes how GSH is not only important as an antioxidant but also as a signaling molecule. There is an extensive literature of the role of GSH in immunity. Most reviews are biased by an oversimplified picture where “bad” free radicals cause all sorts of diseases and “good” antioxidants protect from them and prevent oxidative stress. While this may be the case in certain fields (eg, toxicology, the role of thiols (the topic of this review in immunity certainly requires wearing scientist’s goggles and being prepared to accept a more complex picture. This review aims at describing the role of GSH in the lung in the context of immunity and inflammation. The first part summarizes the history and basic concepts of this picture. The second part focuses on GSH metabolism/levels in pathology, the third on the role of GSH in innate immunity and inflammation, and the fourth gives 4 examples describing the importance of GSH in the response to infections.Keywords: antioxidants, oxidative stress, sepsis, infection, cysteine

  11. Epigenetics and the Adaptive Immune Response

    Kondilis-Mangum, Hrisavgi D.; Wade, Paul A.

    2012-01-01

    Cells of the adaptive immune response undergo dynamic epigenetic changes as they develop and respond to immune challenge. Plasticity is a necessary prerequisite for the chromosomal dynamics of lineage specification, development, and the immune effector function of the mature cell types. The alterations in DNA methylation and histone modification that characterize activation may be integral to the generation of immunologic memory, thereby providing an advantage on secondary exposure to pathoge...

  12. Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation

    Kanczkowski, Waldemar; Alexaki, Vasileia-Ismini; Tran, Nguyen; Großklaus, Sylvia; Zacharowski, Kai; Martinez, Antoine; Popovics, Petra; Norman L Block; Chavakis, Triantafyllos; Schally, Andrew V.; Stefan R Bornstein

    2013-01-01

    In several critically ill patients the homeostatic regulation of adrenocortical hormone secretion is impaired. Toll-like receptors (TLR) play a substantial role in HPA axis activation in the course of systemic inflammation. Here, using mice with conditional deletion of a crucial TLR adapter protein, MyD88, we investigated the role of systemic and local adrenal TLR signaling in the activation of adrenal glucocorticoid responses to stress and regulation of immune-adrenal crosstalk during system...

  13. Modulation of the immune system during postpartum uterine inflammation.

    Walker, Caroline G; Meier, Susanne; Hussein, Hassan; McDougall, Scott; Burke, Chris R; Roche, John R; Mitchell, Murray D

    2015-04-01

    Postpartum uterine inflammation (endometritis) in the dairy cow is associated with lower fertility at both the time of infection and after the inflammation has resolved. We hypothesized that aberrant DNA methylation may be involved in the subfertility associated with uterine inflammation. The objective of this study was to characterize genome-wide DNA methylation and gene expression in the endometrium of dairy cows with subclinical endometritis (SCE). Endometrial tissues were obtained at 29 days postpartum (n = 12), and microarrays were used to characterize transcription and DNA methylation. Analyses revealed 1,856 probes differentially expressed in animals with SCE (n = 6) compared with controls (CON, n = 6, P cows, with the majority related to the immune response. Furthermore, the top ontology terms enriched in genes that had expression data correlated to bacteriology score were: Defense response, inflammatory response, and innate immune response. Gene expression profiles in cows with subclinical endometritis in this study indicate that the immune response is activated, potentially resulting in a local proinflammatory environment in the uterus. If this period of inflammation is prolonged it could result in tissue damage or failure to complete involution of the uterus, which may create a suboptimal environment for future pregnancy. PMID:25604124

  14. The origins of vertebrate adaptive immunity.

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

    2010-08-01

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

  15. Adaptive Immune Evolutionary Algorithms Based on Immune Network Regulatory Mechanism

    HE Hong; QIAN Feng

    2007-01-01

    Based on immune network regulatory mechanism, a new adaptive immune evolutionary algorithm (AIEA) is proposed to improve the performance of genetic algorithms (GA) in this paper. AIEA adopts novel selection operation according to the stimulation level of each antibody. A memory base for good antibodies is devised simultaneously to raise the convergent rapidity of the algorithm and adaptive adjusting strategy of antibody population is used for preventing the loss of the population adversity. The experiments show AIFA has better convergence performance than standard genetic algorithm and is capable of maintaining the adversity of the population and solving function optimization problems in an efficient and reliable way.

  16. Aging of the Immune System: How Much Can the Adaptive Immune System Adapt?

    Weng, Nan-ping

    2006-01-01

    The competency of the adaptive immune function decreases with age, primarily because of the decline in production of naïve lymphocytes in the bone marrow and thymus as well as the expansion of incompetent memory lymphocytes. Here I discuss the recent progress on age-associated changes in lymphocytes and their effect on the adaptive immune system.

  17. Aggravating Impact of Nanoparticles on Immune-Mediated Pulmonary Inflammation

    Ken-Ichiro Inoue; Hirohisa Takano

    2011-01-01

    Although the adverse health effects of nanoparticles have been proposed and are being clarified, their aggravating effects on pre-existing pathological conditions have not been fully investigated. In this review, we provide insights into the immunotoxicity of both airborne and engineered nanoparticles as an exacerbating factor on hypersusceptible subjects, especially those with immune-mediated pulmonary inflammation, using our in vivo experimental model. First, we exhibit the effects of nanop...

  18. Regulation of intestinal homeostasis by innate and adaptive immunity.

    Kayama, Hisako; Takeda, Kiyoshi

    2012-11-01

    The intestine is a unique tissue where an elaborate balance is maintained between tolerance and immune responses against a variety of environmental factors such as food and the microflora. In a healthy individual, the microflora stimulates innate and adaptive immune systems to maintain gut homeostasis. However, the interaction of environmental factors with particular genetic backgrounds can lead to dramatic changes in the composition of the microflora (i.e. dysbiosis). Many of the specific commensal-bacterial products and the signaling pathways they trigger have been characterized. The role of T(h)1, T(h)2 and T(h)17 cells in inflammatory bowel disease has been widely investigated, as has the contribution of epithelial cells and subsets of dendritic cells and macrophages. To date, multiple regulatory cells in adaptive immunity, such as regulatory T cells and regulatory B cells, have been shown to maintain gut homeostasis by preventing inappropriate innate and adaptive immune responses to commensal bacteria. Additionally, regulatory myeloid cells have recently been identified that prevent intestinal inflammation by inhibiting T-cell proliferation. An increasing body of evidence has shown that multiple regulatory mechanisms contribute to the maintenance of gut homeostasis. PMID:22962437

  19. Role of DNA repair in host immune response and inflammation.

    Fontes, Fabrícia Lima; Pinheiro, Daniele Maria Lopes; Oliveira, Ana Helena Sales de; Oliveira, Rayssa Karla de Medeiros; Lajus, Tirzah Braz Petta; Agnez-Lima, Lucymara Fassarella

    2015-01-01

    In recent years, the understanding of how DNA repair contributes to the development of innate and acquired immunity has emerged. The DNA damage incurred during the inflammatory response triggers the activation of DNA repair pathways, which are required for host-cell survival. Here, we reviewed current understanding of the mechanism by which DNA repair contributes to protection against the oxidized DNA damage generated during infectious and inflammatory diseases and its involvement in innate and adaptive immunity. We discussed the functional role of DNA repair enzymes in the immune activation and the relevance of these processes to: transcriptional regulation of cytokines and other genes involved in the inflammatory response; V(D)J recombination; class-switch recombination (CSR); and somatic hypermutation (SHM). These three last processes of DNA damage repair are required for effective humoral adaptive immunity, creating genetic diversity in developing T and B cells. Furthermore, viral replication is also dependent on host DNA repair mechanisms. Therefore, the elucidation of the pathways of DNA damage and its repair that activate innate and adaptive immunity will be important for a better understanding of the immune and inflammatory disorders and developing new therapeutic interventions for treatment of these diseases and for improving their outcome. PMID:25795123

  20. CRISPR adaptive immune systems of Archaea

    Vestergaard, Gisle; Garrett, Roger A.; Shah, Shiraz A.

    2014-01-01

    CRISPR adaptive immune systems were analyzed for all available completed genomes of archaea, which included representatives of each of the main archaeal phyla. Initially, all proteins encoded within, and proximal to, CRISPR-cas loci were clustered and analyzed using a profile–profile approach. Then cas genes were assigned to gene cassettes and to functional modules for adaptation and interference. CRISPR systems were then classified primarily on the basis of their concatenated Cas protein seq...

  1. Control of the adaptive immune response by tumor vasculature

    Laetitia eMauge

    2014-03-01

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

  2. Coincident helminth infection modulates systemic inflammation and immune activation in active pulmonary tuberculosis.

    Parakkal Jovvian George

    Full Text Available Helminth infections are known to modulate innate and adaptive immune responses in active and latent tuberculosis (TB. However, the role of helminth infections in modulating responses associated with inflammation and immune activation (reflecting disease activity and/or severity in TB is not known.We measured markers of inflammation and immune activation in active pulmonary TB individuals (ATB with co-incidental Strongyloides stercoralis (Ss infection. These included systemic levels of acute phase proteins, matrix metalloproteinases and their endogenous inhibitors and immune activation markers. As a control, we measured the systemic levels of the same molecules in TB-uninfected individuals (NTB with or without Ss infection.Our data confirm that ATB is associated with elevated levels of the various measured molecules when compared to those seen in NTB. Our data also reveal that co-incident Ss infection in ATB individuals is associated with significantly decreased circulating levels of acute phase proteins, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases as well as the systemic immune activation markers, sCD14 and sCD163. These changes are specific to ATB since they are absent in NTB individuals with Ss infection.Our data therefore reveal a profound effect of Ss infection on the markers associated with TB disease activity and severity and indicate that co-incidental helminth infections might dampen the severity of TB disease.

  3. Innate Immunity and Inflammation in NAFLD/NASH.

    Arrese, Marco; Cabrera, Daniel; Kalergis, Alexis M; Feldstein, Ariel E

    2016-05-01

    Inflammation and hepatocyte injury and death are the hallmarks of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), which is a currently burgeoning public health problem. Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Thus, identification of the underlying mechanisms by which immune cells in the liver recognize cell damage signals or the presence of pathogens or pathogen-derived factors that activate them is relevant from a therapeutic perspective. In this review, we present new insights into the factors promoting the inflammatory response in NASH including sterile cell death processes resulting from lipotoxicity in hepatocytes as well as into the altered gut-liver axis function, which involves translocation of bacterial products into portal circulation as a result of gut leakiness. We further delineate the key immune cell types involved and how they recognize both damage-associated molecular patterns or pathogen-associated molecular patterns through binding of surface-expressed pattern recognition receptors, which initiate signaling cascades leading to injury amplification. The relevance of modulating these inflammatory signaling pathways as potential novel therapeutic strategies for the treatment of NASH is summarized. PMID:26841783

  4. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis.

    Klose, Christoph S N; Artis, David

    2016-06-21

    Research over the last 7 years has led to the formal identification of innate lymphoid cells (ILCs), increased the understanding of their tissue distribution and has established essential functions of ILCs in diverse physiological processes. These include resistance to pathogens, the regulation of autoimmune inflammation, tissue remodeling, cancer and metabolic homeostasis. Notably, many ILC functions appear to be regulated by mechanisms distinct from those of other innate and adaptive immune cells. In this Review, we focus on how group 2 ILC (ILC2) and group 3 ILC (ILC3) responses are regulated and how these cells interact with other immune and non-immune cells to mediate their functions. We highlight experimental evidence from mouse models and patient-based studies that have elucidated the effects of ILCs on the maintenance of tissue homeostasis and the consequences for health and disease. PMID:27328006

  5. Oxazolone-induced contact hypersensitivity reduces lymphatic drainage but enhances the induction of adaptive immunity.

    David Aebischer

    Full Text Available Contact hypersensitivity (CHS induced by topical application of haptens is a commonly used model to study dermal inflammatory responses in mice. Several recent studies have indicated that CHS-induced skin inflammation triggers lymphangiogenesis but may negatively impact the immune-function of lymphatic vessels, namely fluid drainage and dendritic cell (DC migration to draining lymph nodes (dLNs. On the other hand, haptens have been shown to exert immune-stimulatory activity by inducing DC maturation. In this study we investigated how the presence of pre-established CHS-induced skin inflammation affects the induction of adaptive immunity in dLNs. Using a mouse model of oxazolone-induced skin inflammation we observed that lymphatic drainage was reduced and DC migration from skin to dLNs was partially compromised. At the same time, a significantly stronger adaptive immune response towards ovalbumin (OVA was induced when immunization had occurred in CHS-inflamed skin as compared to uninflamed control skin. In fact, immunization with sterile OVA in CHS-inflamed skin evoked a delayed-type hypersensitivity (DTH response comparable to the one induced by conventional immunization with OVA and adjuvant in uninflamed skin. Striking phenotypic and functional differences were observed when comparing DCs from LNs draining uninflamed or CHS-inflamed skin. DCs from LNs draining CHS-inflamed skin expressed higher levels of co-stimulatory molecules and MHC molecules, produced higher levels of the interleukin-12/23 p40 subunit (IL-12/23-p40 and more potently induced T cell activation in vitro. Immunization experiments revealed that blockade of IL-12/23-p40 during the priming phase partially reverted the CHS-induced enhancement of the adaptive immune response. Collectively, our findings indicate that CHS-induced skin inflammation generates an overall immune-stimulatory milieu, which outweighs the potentially suppressive effect of reduced lymphatic vessel function.

  6. The aging of the adaptive immune system

    Grubeck-Loebenstein, B.; Weinberger, B.; Herndler-Brandstetter, D.; Weiskopf, D.; Pfister, G.

    2011-01-01

    Adaptive immune responses are severely affected by the aging process as reflected by an increased morbidity and mortality from infectious diseases and a low efficacy of vaccination in elderly persons. Age-related changes within the bone marrow and thymus lead to an impaired generation of new T and B cells severely compromising the maintenance of a diverse and balanced T and B cell repertoire in old age. The maintenance of a balanced T cell repertoire is further challenged by latent persistent...

  7. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis

    Balestro, Elisabetta; Calabrese, Fiorella; Turato, Graziella; Lunardi, Francesca; Bazzan, Erica; Marulli, Giuseppe; Biondini, Davide; Rossi, Emanuela; Sanduzzi, Alessandro; Rea, Federico; Rigobello, Chiara; Gregori, Dario; Baraldo, Simonetta; Spagnolo, Paolo

    2016-01-01

    The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define “slow” or “rapid” disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression. PMID:27159038

  8. Chemokine-guided cell positioning in the lymph node orchestrates the generation of adaptive immune responses.

    Lian, Jeffrey; Luster, Andrew D

    2015-10-01

    The generation of adaptive immune responses occurs in the lymph node (LN) and requires that lymphocytes locate and interact with cognate antigen-bearing dendritic cells. This process requires the coordinated movement of both innate and adaptive immune cells, and is orchestrated by the chemokine family of chemotactic cytokines. Upon initiation of inflammation, the LN undergoes dramatic changes that include the marked induction of specific chemokines in distinct regions of the reactive LN. These chemokine rich domains establish LN niches that facilitate the differentiation of CD4+ T cells into effector cell subsets and the rapid activation of memory CD8+ T cells. This review will focus on recent advances highlighting the importance of LN chemokines for shaping adaptive immune responses by controlling immune cell migration, positioning, and interactions in the reactive LN. PMID:26067148

  9. Immunoglobulin E and Allergy: Antibodies in Immune Inflammation and Treatment.

    Karagiannis, Sophia N; Karagiannis, Panagiotis; Josephs, Debra H; Saul, Louise; Gilbert, Amy E; Upton, Nadine; Gould, Hannah J

    2013-10-01

    The pathogenic role of immunoglobulin E (IgE) antibodies in triggering and maintaining allergic inflammation in response to allergens is due to the binding of multivalent allergens to allergen-specific IgEs on sensitized effector cells. These interactions trigger effector cell activation, resulting in release of potent inflammatory mediators, recruitment of inflammatory cells, antigen presentation, and production of allergen-specific antibody responses. Since its discovery in the 1960s, the central role of IgE in allergic disease has been intensively studied, placing IgE and its functions at the heart of therapeutic efforts for the treatment of allergies. Here, we provide an overview of the nature, roles, and significance of IgE antibodies in allergic diseases, infections, and inflammation and the utility of antibodies as therapies. We place special emphasis on allergen-IgE-Fcε receptor complexes in the context of allergic and inflammatory diseases and describe strategies, including monoclonal antibodies, aimed at interrupting these complexes. Of clinical significance, one antibody, omalizumab, is presently in clinical use and works by preventing formation of IgE-Fcε receptor interactions. Active immunotherapy approaches with allergens and allergen derivatives have also demonstrated clinical benefits for patients with allergic diseases. These treatments are strongly associated with serum increases of IgE-neutralizing antibodies and feature a notable redirection of humoral responses towards production of antibodies of the IgG4 subclass in patients receiving immunotherapies. Lastly, we provide a new perspective on the rise of recombinant antibodies of the IgE class recognizing tumor-associated antigens, and we discuss the potential utility of tumor antigen-specific IgE antibodies to direct potent IgE-driven immune responses against tumors. PMID:26184813

  10. Role of protein tyrosine phosphatases in regulating the immune system: implications for chronic intestinal inflammation.

    Spalinger, Marianne R; McCole, Declan F; Rogler, Gerhard; Scharl, Michael

    2015-03-01

    Current hypothesis suggests that genetic, immunological, and bacterial factors contribute essentially to the pathogenesis of inflammatory bowel disease. Variations within the gene loci encoding protein tyrosine phosphatases (PTPs) have been associated with the onset of inflammatory bowel disease. PTPs modulate the activity of their substrates by dephosphorylation of tyrosine residues and are critical for the regulation of fundamental cellular signaling processes. Evidence emerges that expression levels of PTPN2, PTPN11, and PTPN22 are altered in actively inflamed intestinal tissue. PTPN2 seems to be critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses and finally for maintaining intestinal homeostasis. These observations have been confirmed in PTPN2 knockout mice in vivo. Those animals are clearly more susceptible to intestinal and systemic inflammation and feature alterations in innate and adaptive immune responses. PTPN22 controls inflammatory signaling in lymphocytes and mononuclear cells resulting in aberrant cytokine secretion pattern and autophagosome formation. PTPN22 deficiency in vivo results in more severe colitis demonstrating the relevance of PTPN22 for intestinal homeostasis in vivo. Of note, loss of PTPN22 promotes mitogen-activated protein kinase-induced cytokine secretion but limits secretion of nuclear factor κB-associated cytokines and autophagy in mononuclear cells. Loss of PTPN11 is also associated with increased colitis severity in vivo. In summary, dysfunction of those PTPs results in aberrant and uncontrolled immune responses that result in chronic inflammatory conditions. This way, it becomes more and more evident that dysfunction of PTPs displays an important factor in the pathogenesis of chronic intestinal inflammation, in particular inflammatory bowel disease. PMID:25581833

  11. Chronic infection and the origin of adaptive immune system

    Usharauli, David

    2010-01-01

    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 ...

  12. TLR4 signalling in pulmonary stromal cells is critical for inflammation and immunity in the airways

    Lambrecht Bart N

    2011-09-01

    Full Text Available Abstract Inflammation of the airways, which is often associated with life-threatening infection by Gram-negative bacteria or presence of endotoxin in the bioaerosol, is still a major cause of severe airway diseases. Moreover, inhaled endotoxin may play an important role in the development and progression of airway inflammation in asthma. Pathologic changes induced by endotoxin inhalation include bronchospasm, airflow obstruction, recruitment of inflammatory cells, injury of the alveolar epithelium, and disruption of pulmonary capillary integrity leading to protein rich fluid leak in the alveolar space. Mammalian Toll-like receptors (TLRs are important signalling receptors in innate host defense. Among these receptors, TLR4 plays a critical role in the response to endotoxin. Lungs are a complex compartmentalized organ with separate barriers, namely the alveolar-capillary barrier, the microvascular endothelium, and the alveolar epithelium. An emerging theme in the field of lung immunology is that structural cells (SCs of the airways such as epithelial cells (ECs, endothelial cells, fibroblasts and other stromal cells produce activating cytokines that determine the quantity and quality of the lung immune response. This review focuses on the role of TLR4 in the innate and adaptive immune functions of the pulmonary SCs.

  13. Adaptive immune responses of legumin nanoparticles.

    Mirshahi, T; Irache, J M; Nicolas, C; Mirshahi, M; Faure, J P; Gueguen, J; Hecquet, C; Orecchioni, A M

    2002-12-01

    Legumin is one of the main storage proteins in the pea seeds (Pisum sativum L.) and the molecules of this protein have the capacity of binding together to form nanoparticles after aggregation and chemical cross-linkage with glutaraldehyde. The aim of this work was to study the adaptive immune response of legumin nanoparticles in rats. Following intradermal immunisation with the native protein legumin and legumin nanoparticles of about 250 nm, the humoral and cell-mediated immune responses were analysed in rats. The humoral responses against legumin and legumin nanoparticles were examined by western blot and ELISA analysis. Both techniques clearly showed that sera from rats immunised with legumin strongly expressed antibodies against this protein. On the contrary, serum samples from rats inoculated with legumin nanoparticles did not contain detectable amounts of antibodies. These results may be explained by a reduction on the antigenic epitopes of the protein induced by the glutaraldehyde used during the cross-linking step. Concerning the cell-mediated response, neither legumin nor legumin nanoparticles stimulated an immunogenic response. This absence of response of spleen lymphocytes for legumin and legumin nanoparticles may be explained by a cytostatic effect of legumin which was corroborated by the evaluation of the middle phase of cell apoptose. In fact, both legumin and legumin nanoparticles are potent inductors of a cytostatic phenomenon and showed a significant increase of the chromatin condensation (p < 0.05) as compared with control. PMID:12683667

  14. The Immunobiology of Prostanoid Receptor Signaling in Connecting Innate and Adaptive Immunity

    Hedi Harizi

    2013-01-01

    Full Text Available Prostanoids, including prostaglandins (PGs, thromboxanes (TXs, and prostacyclins, are synthesized from arachidonic acid (AA by the action of Cyclooxygenase (COX enzymes. They are bioactive inflammatory lipid mediators that play a key role in immunity and immunopathology. Prostanoids exert their effects on immune and inflammatory cells by binding to membrane receptors that are widely expressed throughout the immune system and act at multiple levels in innate and adaptive immunity. The immunoregulatory role of prostanoids results from their ability to regulate cell-cell interaction, antigen presentation, cytokine production, cytokine receptor expression, differentiation, survival, apoptosis, cell-surface molecule levels, and cell migration in both autocrine and paracrine manners. By acting on immune cells of both systems, prostanoids and their receptors have great impact on immune regulation and play a pivotal role in connecting innate and adaptive immunity. This paper focuses on the immunobiology of prostanoid receptor signaling because of their potential clinical relevance for various disorders including inflammation, autoimmunity, and tumorigenesis. We mainly discuss the effects of major COX metabolites, PGD2, PGE2, their signaling during dendritic cell (DC-natural killer (NK reciprocal crosstalk, DC-T cell interaction, and subsequent consequences on determining crucial aspects of innate and adaptive immunity in normal and pathological settings.

  15. Proximity to Traffic, Inflammation, and Immune Function among Women in the Seattle, Washington, Area

    Williams, Lori A.; Ulrich, Cornelia M.; Larson, Timothy; Wener, Mark H.; Wood, Brent; Campbell, Peter T.; Potter, John D.; McTiernan, Anne; De Roos, Anneclaire J

    2008-01-01

    Background Traffic-related air pollution has been associated with adverse health outcomes, and the immune system may be a biologic mediator of health effects. Objectives We analyzed associations between living near major roads and immune status as measured by five immune assays. We hypothesized that living near a freeway, arterial, or truck route would be associated with increased inflammation and decreased immune function. Methods We used a geographic information system (GIS) to determine re...

  16. Treatment of autoimmune inflammation by a TLR7 ligand regulating the innate immune system.

    Tomoko Hayashi

    Full Text Available The Toll-like receptors (TLR have been advocated as attractive therapeutic targets because TLR signaling plays dual roles in initiating adaptive immune responses and perpetuating inflammation. Paradoxically, repeated stimulation of bone marrow mononuclear cells with a synthetic TLR7 ligand 9-benzyl-8-hydroxy-2-(2-methoxyethoxy adenine (called 1V136 leads to subsequent TLR hyporesponsiveness. Further studies on the mechanism of action of this pharmacologic agent demonstrated that the TLR7 ligand treatment depressed dendritic cell activation, but did not directly affect T cell function. To verify this mechanism, we utilized experimental allergic encephalitis (EAE as an in vivo T cell dependent autoimmune model. Drug treated SJL/J mice immunized with proteolipid protein (PLP(139-151 peptide had attenuated disease severity, reduced accumulation of mononuclear cells in the central nervous system (CNS, and limited demyelination, without any apparent systemic toxicity. Splenic T cells from treated mice produced less cytokines upon antigenic rechallenge. In the spinal cords of 1V136-treated EAE mice, the expression of chemoattractants was also reduced, suggesting innate immune cell hyposensitization in the CNS. Indeed, systemic 1V136 did penetrate the CNS. These experiments indicated that repeated doses of a TLR7 ligand may desensitize dendritic cells in lymphoid organs, leading to diminished T cell responses. This treatment strategy might be a new modality to treat T cell mediated autoimmune diseases.

  17. Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging

    Giovanoli, Sandra; Notter, Tina; Richetto, Juliet; Labouesse, Marie A.; Vuillermot, Stéphanie; Riva, Marco A; Meyer, Urs

    2015-01-01

    Background Prenatal exposure to infection and/or inflammation is increasingly recognized to play an important role in neurodevelopmental brain disorders. It has recently been postulated that prenatal immune activation, especially when occurring during late gestational stages, may also induce pathological brain aging via sustained effects on systemic and central inflammation. Here, we tested this hypothesis using an established mouse model of exposure to viral-like immune activation in late pr...

  18. Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in humans

    Line Larry L; Kim Yoo; Chyun Jong; Park Jean; Chew Boon P

    2010-01-01

    Abstract Background Astaxanthin modulates immune response, inhibits cancer cell growth, reduces bacterial load and gastric inflammation, and protects against UVA-induced oxidative stress in in vitro and rodent models. Similar clinical studies in humans are unavailable. Our objective is to study the action of dietary astaxanthin in modulating immune response, oxidative status and inflammation in young healthy adult female human subjects. Methods Participants (averaged 21.5 yr) received 0, 2, o...

  19. Role of SHIP-1 in the adaptive immune responses to aeroallergen in the airway.

    Sukit Roongapinun

    Full Text Available BACKGROUND: Th2-dominated inflammatory response in the airway is an integral component in the pathogenesis of allergic asthma. Accumulating evidence supports the notion that the phosphoinositide 3-kinase (PI3K pathway is involved in the process. We previously reported that SHIP-1, a negative regulator of the PI3K pathway, is essential in maintaining lung immunohomeostasis, potentially through regulation of innate immune cells. However, the function of SHIP-1 in adaptive immune response in the lung has not been defined. We sought to determine the role of SHIP-1 in adaptive immunity in response to aeroallergen stimulation in the airway. METHODOLOGY/PRINCIPAL FINDINGS: SHIP-1 knockout (SHIP-1-/- mice on BALB/c background were immunized with ovalbumin (OVA plus aluminum hydroxide, a strong Th2-inducing immunization, and challenged with OVA. Airway and lung inflammation, immunoglobulin response, Th2 cytokine production and lymphocyte response were analyzed and compared with wild type mice. Even though there was mild spontaneous inflammation in the lung at baseline, SHIP-1-/- mice showed altered responses, including less cell infiltration around the airways but more in the parenchyma, less mucus production, decreased Th2 cytokine production, and diminished serum OVA-specific IgE, IgG1, but not IgG2a. Naïve and OVA sensitized SHIP-1-/- T cells produced a lower amount of IL-4. In vitro differentiated SHIP-1-/- Th2 cells produced less IL-4 compared to wild type Th2 cells upon T cell receptor stimulation. CONCLUSIONS/SIGNIFICANCE: These findings indicate that, in contrast to its role as a negative regulator in the innate immune cells, SHIP-1 acts as a positive regulator in Th2 cells in the adaptive immune response to aeroallergen. Thus any potential manipulation of SHIP-1 activity should be adjusted according to the specific immune response.

  20. Scale-free dynamics of somatic adaptability in immune system

    Saito, Shiro

    2009-01-01

    The long-time dynamics of somatic adaptability in immune system is simulated by a simple physical model. The immune system described by the model exhibits a scale free behavior as is observed in living systems. The balance between the positive and negative feedbacks of the model leads to a robust immune system where the positive one corresponds to the formation of memory cells and the negative one to immunosuppression. Also the immunosenescence of the system is discussed based on the time-dependence of the epigenetic landscape of the adaptive immune cells in the shape space.

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

    Dominique M. A. Bullens

    2013-01-01

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

  2. Complement activation pathways: a bridge between innate and adaptive immune responses in asthma.

    Wills-Karp, Marsha

    2007-07-01

    Although it is widely accepted that allergic asthma is driven by T helper type 2 (Th2)-polarized immune responses to innocuous environmental allergens, the mechanisms driving these aberrant immune responses remain elusive. Recent recognition of the importance of innate immune pathways in regulating adaptive immune responses have fueled investigation into the role of innate immune pathways in the pathogenesis of asthma. The phylogenetically ancient innate immune system, the complement system, is no exception. The emerging paradigm is that C3a production at the airway surface serves as a common pathway for the induction of Th2-mediated inflammatory responses to a variety of environmental triggers of asthma (i.e., allergens, pollutants, viral infections, cigarette smoke). In contrast, C5a plays a dual immunoregulatory role by protecting against the initial development of a Th2-polarized adaptive immune response via its ability to induce tolerogenic dendritic cell subsets. On the other hand, C5a drives type 2-mediated inflammatory responses once inflammation ensues. Thus, alterations in the balance of generation of the various components of the complement pathway either due to environmental exposure changes or genetic alterations in genes of the complement cascade may underlie the recent rise in asthma prevalence in westernized countries. PMID:17607007

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

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

    2016-08-01

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

  4. Donor-derived exosomes induce specific regulatory T cells to suppress immune inflammation in the allograft heart

    Jiangping Song; Jie Huang; Xiao Chen; Xiao Teng; Zhizhao Song; Yong Xing; Mangyuan Wang; Kai Chen; Zheng Wang; Pingchang Yang; Shengshou Hu

    2016-01-01

    To inhibit the immune inflammation in the allografts can be beneficial to organ transplantation. This study aims to induce the donor antigen specific regulatory T cells (Treg cell) inhibit the immune inflammation in the allograft heart. In this study, peripheral exosomes were purified from the mouse serum. A heart transplantation mouse model was developed. The immune inflammation of the allograft heart was assessed by histology and flow cytometry. The results showed that the donor antigen-spe...

  5. CRISPR-Based Adaptive Immune Systems

    Terns, Michael P.; Terns, Rebecca M.

    2011-01-01

    CRISPR-Cas systems are recently discovered, RNA-based immune systems that control invasions of viruses and plasmids in archaea and bacteria. Prokaryotes with CRISPR-Cas immune systems capture short invader sequences within the CRISPR loci in their genomes, and small RNAs produced from the CRISPR loci (CRISPR (cr)RNAs) guide Cas proteins to recognize and degrade (or otherwise silence) the invading nucleic acids. There are multiple variations of the pathway found among prokaryotes, each mediate...

  6. Phylogeny, longevity and evolution of adaptive immunity

    Vinkler, Michal; Albrecht, Tomáš

    2011-01-01

    Roč. 60, č. 3 (2011), s. 277-282. ISSN 0139-7893 R&D Projects: GA ČR GA206/08/0640; GA ČR GA206/08/1281; GA ČR GAP505/10/1871 Institutional research plan: CEZ:AV0Z60930519 Keywords : acquired immunity * evolutionary immunology * immunological priming * innate immunity * invertebrates Subject RIV: EG - Zoology Impact factor: 0.554, year: 2011

  7. Immunsystemet ved kronisk inflammation

    Bendtzen, Klaus

    2008-01-01

    Innate and adaptive immunity has evolved as a defence against infections and as an important repair mechanism after physical injury. If elimination of microbes and healing is not achieved, or if the immune system is dysregulated, chronic inflammation ensues. Immune cells become engaged in prolonged...

  8. Macrophages Subvert Adaptive Immunity to Urinary Tract Infection.

    Gabriela Mora-Bau

    2015-07-01

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

  9. INNATE, ADAPTIVE AND INTRINSIC IMMUNITY IN HUMAN IMMUNODEFICIENCY VIRUS INFECTION

    Suneth S. Perera

    2012-01-01

    Full Text Available The first line of defence of the innate immune system functions by recognizing highly conserved sets of molecular structures specific to the microbes, termed pathogen-associated molecular patterns, or PAMPs via the germ line-encoded receptors Pattern-Recognition Receptors (PRRs. In addition to the innate immune system, the vertebrates have also evolved a second line of defence termed adaptive immune system, which uses a diverse set of somatically rearranged receptors T-Cell Receptors (TCRs and B Cell Receptors (BCRs, which have the inherent ability to effectively recognise diverse antigens. The innate and adaptive immune systems are functionally tied in with the intrinsic immunity, which comprises of endogenous antiviral factors. Thus, this effective response to diverse microbial infections, including HIV, requires a coordinated interaction at several functional levels between innate, adaptive and intrinsic immune systems. This review provides a snapshot of roles played by the innate, adaptive and the intrinsic immune systems during HIV-infection, along with discussing recent developments highlighting the genomic basis of these responses and their regulation by micro-RNA (miRNAs.

  10. Therapeutics targeting inflammation in the immune reconstitution inflammatory syndrome.

    Shahani, Lokesh; Hamill, Richard J

    2016-01-01

    Immune reconstitution inflammatory syndrome (IRIS) is characterized by improvement in a previously incompetent human immune system manifesting as worsening of clinical symptoms secondary to the ability of the immune system to now mount a vigorous inflammatory response. IRIS was first recognized in the setting of human immunodeficiency virus, and this clinical setting continues to be where it is most frequently encountered. Hallmarks of the pathogenesis of IRIS, independent of the clinical presentation and the underlying pathogen, include excessive activation of the immune system, with increased circulating effector memory T cells, and elevated levels of serum cytokines and inflammatory markers. Patients with undiagnosed opportunistic infections remain at risk for unmasking IRIS at the time of active antiretroviral therapy (ART) initiation. Systematic screening for opportunistic infections before starting ART is a key element to prevent this phenomenon. Appropriate management of IRIS requires prompt recognition of the syndrome and exclusion of alternative diagnoses, particularly underlying infections and drug resistance. Controlled studies supporting the use of pharmacologic interventions in IRIS are scare, and recommendations are based on case series and expert opinions. The only controlled trial published to date, showed reduction in morbidity in patients with paradoxical tuberculosis-related IRIS with the use of oral corticosteroids. There are currently limited data to recommend other anti-inflammatory or immunomodulatory therapies that are discussed in this review, and further research is needed. Ongoing research regarding the immune pathogenesis of IRIS will likely direct future rational therapeutic approaches and clinical trials. PMID:26303886

  11. Crosstalk between innate and adaptive immunity inhepatitis B virus infection

    2015-01-01

    Hepatitis B virus (HBV) infection is a major public health problem worldwide. HBV is not directly cytotoxic toinfected hepatocytes; the clinical outcome of infectionresults from complicated interactions between the virusand the host immune system. In acute HBV infection,initiation of a broad, vigorous immune response is responsiblefor viral clearance and self-limited inflammatoryliver disease. Effective and coordinated innate andadaptive immune responses are critical for viral clearanceand the development of long-lasting immunity. Chronichepatitis B patients fail to mount efficient innate andadaptive immune responses to the virus. In particular,HBV-specific cytotoxic T cells, which are crucial for HBVclearance, are hyporesponsiveness to HBV infection.Accumulating experimental evidence obtained fromthe development of animal and cell line models hashighlighted the importance of innate immunity in theearly control of HBV spread. The virus has evolvedimmune escape strategies, with higher HBV loads andHBV protein concentrations associated with increasingimpairment of immune function. Therefore, treatmentof HBV infection requires inhibition of HBV replicationand protein expression to restore the suppressedhost immunity. Complicated interactions exist notonly between innate and adaptive responses, but alsoamong innate immune cells and different components ofadaptive responses. Improved insight into these complexinteractions are important in designing new therapeuticstrategies for the treatment HBV infection. In thisreview, we summarize the current knowledge regardingthe cross-talk between the innate and adaptive immuneresponses and among different immunocytes in HBVinfection.

  12. Immunoregulatory molecules are master regulators of inflammation during the immune response

    de la Fuente, Hortensia; Cibrián, Danay; Sánchez-Madrid, Francisco

    2012-01-01

    The balance between pro- and anti-inflammatory signalling is critical to maintain the immune homeostasis under physiological conditions as well as for the control of inflammation in different pathological settings. Recent progress in the signalling pathways that control this balance has led to the development of novel therapeutic agents for diseases characterized by alterations in the activation/suppression of the immune response. Different molecules have a key role in the regulation of the i...

  13. Innate Lymphoid Cells: Balancing Immunity, Inflammation, and Tissue Repair in the Intestine

    Wojno, Elia D. Tait; Artis, David

    2012-01-01

    Innate lymphoid cells (ILCs) are a recently described group of innate immune cells that can regulate immunity, inflammation, and tissue repair in multiple anatomical compartments, particularly the barrier surfaces of the skin, airways, and intestine. Broad categories of ILCs have been defined based on transcription factor expression and the ability to produce distinct patterns of effector molecules. Recent studies have revealed that ILC populations can regulate commensal bacterial communities...

  14. Immune genes undergo more adaptive evolution than non-immune system genes in Daphnia pulex

    McTaggart Seanna J

    2012-05-01

    Full Text Available Abstract Background Understanding which parts of the genome have been most influenced by adaptive evolution remains an unsolved puzzle. Some evidence suggests that selection has the greatest impact on regions of the genome that interact with other evolving genomes, including loci that are involved in host-parasite co-evolutionary processes. In this study, we used a population genetic approach to test this hypothesis by comparing DNA sequences of 30 putative immune system genes in the crustacean Daphnia pulex with 24 non-immune system genes. Results In support of the hypothesis, results from a multilocus extension of the McDonald-Kreitman (MK test indicate that immune system genes as a class have experienced more adaptive evolution than non-immune system genes. However, not all immune system genes show evidence of adaptive evolution. Additionally, we apply single locus MK tests and calculate population genetic parameters at all loci in order to characterize the mode of selection (directional versus balancing in the genes that show the greatest deviation from neutral evolution. Conclusions Our data are consistent with the hypothesis that immune system genes undergo more adaptive evolution than non-immune system genes, possibly as a result of host-parasite arms races. The results of these analyses highlight several candidate loci undergoing adaptive evolution that could be targeted in future studies.

  15. Tumor Necrosis Factor Superfamily in Innate Immunity and Inflammation

    Šedý, John; Bekiaris, Vasileios; Ware, Carl F.

    2014-01-01

    The tumor necrosis factor superfamily (TNFSF) and its corresponding receptor superfamily (TNFRSF) form communication pathways required for developmental, homeostatic, and stimulus-responsive processes in vivo. Although this receptor–ligand system operates between many different cell types and organ systems, many of these proteins play specific roles in immune system function. The TNFSF and TNFRSF proteins lymphotoxins, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and comp...

  16. Avian Influenza Viruses, Inflammation, and CD8+ T Cell Immunity

    Wang, Zhongfang; Loh, Liyen; Kedzierski, Lukasz; Kedzierska, Katherine

    2016-01-01

    Avian influenza viruses (AIVs) circulate naturally in wild aquatic birds, infect domestic poultry, and are capable of causing sporadic bird-to-human transmissions. AIVs capable of infecting humans include a highly pathogenic AIV H5N1, first detected in humans in 1997, and a low pathogenic AIV H7N9, reported in humans in 2013. Both H5N1 and H7N9 cause severe influenza disease in humans, manifested by acute respiratory distress syndrome, multi-organ failure, and high mortality rates of 60% and 35%, respectively. Ongoing circulation of H5N1 and H7N9 viruses in wild birds and poultry, and their ability to infect humans emphasizes their epidemic and pandemic potential and poses a public health threat. It is, thus, imperative to understand the host immune responses to the AIVs so we can control severe influenza disease caused by H5N1 or H7N9 and rationally design new immunotherapies and vaccines. This review summarizes our current knowledge on AIV epidemiology, disease symptoms, inflammatory processes underlying the AIV infection in humans, and recent studies on universal pre-existing CD8+ T cell immunity to AIVs. Immune responses driving the host recovery from AIV infection in patients hospitalized with severe influenza disease are also discussed. PMID:26973644

  17. Occupational exposure alters innate and adaptive immune responses

    Sahlander, Karin

    2010-01-01

    The farming environment is contaminated with high levels of organic dust. Especially pig barn facilities are highly polluted with airborne inhalable organic dust containing high amounts of molecular patterns from bacteria and fungi known to activate cells of the innate immunity through pattern recognition receptors (PRRs). Some hours of exposure in pig barn environment leads to an intensive upper and lower airway inflammation with systemic influences in previously unexposed ...

  18. Use of genetically modified bacteria to modulate adaptive immunity.

    Bueno, Susan M; González, Pablo A; Kalergis, Alexis M

    2009-06-01

    Infectious diseases caused by virulent bacteria are a significant cause of morbidity and mortality worldwide, especially in developing countries. However, attenuated strains derived from pathogenic bacteria, such as Salmonella, are highly immunogenic and can be used as vaccines to promote immunity against parental pathogenic bacteria strains. Further, they can be genetically manipulated to either express foreign antigens or deliver exogenous DNA, in order to induce immunity against other pathogens or antigens. Contrarily, specific structural modifications in attenuated Salmonella have allowed the generation of strains that can be well tolerated by the immune system and reduce inflammatory responses. It is thought that those strains could be considered as vectors to promote specific immune tolerance for certain auto-antigens or allergens and reduce unwanted or self-reactive immune responses. In addition, some structural features of Salmonella can contribute to defining the nature and type of polarization of the adaptive immune response induced after immunization, which can be considered as a tool to modulate antigen-specific immunity. In this article we discuss recent advances in the understanding of immune system modulation by molecular components of bacteria and their exploitation for the rational induction of pathogen immunity or antigen-specific tolerance. PMID:19519362

  19. Latest recognition of NF-KB'S essential roles in immune, inflammation and apoptosis

    2006-01-01

    Studying the NF-κB-signaling-associated cytoplasm regulation is pivotal for understanding the mechanism of disorders and will provide an attractive target for new intervention and therapy methods. Here we briefly review the latest studies about NF-κB's roles in immunity, inflammation, apoptosis and other pathophysiological processes. These may provide useful evidences for the design of effective therapeutic strategies.

  20. Functional demonstration of adaptive immunity in zebrafish using DNA vaccination

    Lorenzen, Niels; Lorenzen, Ellen; Einer-Jensen, Katja; Rasmussen, Jesper Skou; Kjær, Torben Egil; Vesely, Thomas

    Due to the well characterized genome, overall highly synteny with the human genome and its suitability for functional genomics studies, the zebrafish is considered to be an ideal animal model for basic studies of mechanisms of diseases and immunity in vertebrates including humans. While several...... studies have documented existence of a classical innate immune response, there is mainly indirect evidence of functional adaptive immunity. To address this aspect, groups of zebrafish were vaccinated with DNA-vaccines against the rhabdoviruses VHSV, IHNV and SVCV. Seven weeks later, the fish were...... challenged with SVCV by immersion. Despite some variability between replicate aquaria, there was a protective effect of the homologous vaccine and no effect of the heterologous vaccines. The results therefore confirm the existence of not only a well developed but also a fully functional adaptive immune...

  1. Quantifying adaptive evolution in the Drosophila immune system.

    Darren J Obbard

    2009-10-01

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

  2. Adaptive social immunity in leaf-cutting ants

    Walker, Tom N.; Hughes, William O. H.

    2009-01-01

    Social insects have evolved a suite of sophisticated defences against parasites. In addition to the individual physiological immune response, social insects also express ‘social immunity’ consisting of group-level defences and behaviours that include allogrooming. Here we investigate whether the social immune response of the leaf-cutting ant Acromyrmex echinatior reacts adaptively to the virulent fungal parasite, Metarhizium anisopliae. We ‘immunized’ mini-nests of the ants by exposing them t...

  3. Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective

    Silke Neumann

    2015-12-01

    Full Text Available Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer’s disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells.

  4. Proteasome function shapes innate and adaptive immune responses.

    Kammerl, Ilona E; Meiners, Silke

    2016-08-01

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

  5. Autophagy, inflammation and innate immunity in inflammatory myopathies.

    Cristina Cappelletti

    Full Text Available Autophagy has a large range of physiological functions and its dysregulation contributes to several human disorders, including autoinflammatory/autoimmune diseases such as inflammatory myopathies (IIMs. In order to better understand the pathogenetic mechanisms of these muscular disorders, we sought to define the role of autophagic processes and their relation with the innate immune system in the three main subtypes of IIM, specifically sporadic inclusion body myositis (sIBM, polymyositis (PM, dermatomyositis (DM and juvenile dermatomyositis (JDM. We found that although the mRNA transcript levels of the autophagy-related genes BECN1, ATG5 and FBXO32 were similar in IIM and controls, autophagy activation in all IIM subgroups was suggested by immunoblotting results and confirmed by immunofluorescence. TLR4 and TLR3, two potent inducers of autophagy, were highly increased in IIM, with TLR4 transcripts significantly more expressed in PM and DM than in JDM, sIBM and controls, and TLR3 transcripts highly up-regulated in all IIM subgroups compared to controls. Co-localization between autophagic marker, LC3, and TLR4 and TLR3 was observed not only in sIBM but also in PM, DM and JDM muscle tissues. Furthermore, a highly association with the autophagic processes was observed in all IIM subgroups also for some TLR4 ligands, endogenous and bacterial HSP60, other than the high-mobility group box 1 (HMGB1. These findings indicate that autophagic processes are active not only in sIBM but also in PM, DM and JDM, probably in response to an exogenous or endogenous 'danger signal'. However, autophagic activation and regulation, and also interaction with the innate immune system, differ in each type of IIM. Better understanding of these differences may lead to new therapies for the different IIM types.

  6. Endotoxemia is associated with altered innate and adaptive immune responses in untreated HIV-1 infected individuals.

    Anne Roslev Bukh

    Full Text Available BACKGROUND: Microbial translocation may contribute to the immunopathogenesis in HIV infection. We investigated if microbial translocation and inflammation were associated with innate and adaptive immune responses in adults with HIV. METHODOLOGY/PRINCIPAL FINDINGS: This was an observational cohort study. Sera from HIV-infected and HIV-uninfected individuals were analyzed for microbial translocation (soluble CD14, lipopolysaccharides [LPS], endotoxin core antibody, and anti-α-galactosyl antibodies and inflammatory markers (high sensitivity C-reactive protein, IL-6, IL-1 receptor antagonist, soluble tumor necrosis factor receptor II, and IL-10 with enzyme-linked immunosorbent assays. Peripheral blood mononuclear cells (PBMC from HIV-infected persons and healthy controls (primed with single-stranded HIV-1-derived RNA were stimulated with LPS, and cytokine production was measured. Finally, HIV-infected patients were immunized with Prevnar 7vPnC±CpG 7909 followed by Pneumo Novum PPV-23. Effects of microbial translocation and inflammation on immunization were analyzed in a predictive regression model. We included 96 HIV-infected individuals, 76 on highly active antiretroviral therapy (HAART, 20 HAART-naive, and 50 healthy controls. Microbial translocation and inflammatory markers were higher among HIV-infected persons than controls. Cytokine levels following LPS stimulation were increased in PBMCs from HAART-naive compared to HAART-treated HIV-infected persons. Further, RNA-priming of PBMCs from controls acted synergistically with LPS to augment cytokine responses. Finally, high serum LPS levels predicted poor vaccine responses among HAART-naive, but not among HAART-treated HIV-infected individuals. CONCLUSIONS/SIGNIFICANCE: LPS acts synergistically with HIV RNA to stimulate innate immune responses in vitro and increasing serum LPS levels seem to predict poor antibody responses after vaccination among HAART-naive HIV-infected persons. Thus, our

  7. The Gut Epithelial Receptor LRRC19 Promotes the Recruitment of Immune Cells and Gut Inflammation.

    Cao, Shuisong; Su, Xiaomin; Zeng, Benhua; Yan, Hui; Huang, Yugang; Wang, Enlin; Yun, Huan; Zhang, Yuan; Liu, Feifei; Li, Wenxia; Wei, Hong; Che, Yongzhe; Yang, Rongcun

    2016-02-01

    Commensal microbes are necessary for a healthy gut immune system. However, the mechanism involving these microbes that establish and maintain gut immune responses is largely unknown. Here, we have found that the gut immune receptor leucine-rich repeat (LRR) C19 is involved in host-microbiota interactions. LRRC19 deficiency not only impairs the gut immune system but also reduces inflammatory responses in gut tissues. We demonstrate that the LRRC19-associated chemokines CCL6, CCL9, CXCL9, and CXCL10 play a critical role in immune cell recruitment and intestinal inflammation. The expression of these chemokines is associated with regenerating islet-derived (REG) protein-mediated microbiotas. We also found that the expression of REGs may be regulated by gut Lactobacillus through LRRC19-mediated activation of NF-κB. Therefore, our study establishes a regulatory axis of LRRC19, REGs, altered microbiotas, and chemokines for the recruitment of immune cells and the regulation of intestinal inflammation. PMID:26776522

  8. Multiple sclerosis and fatigue: A review on the contribution of inflammation and immune-mediated neurodegeneration.

    Patejdl, Robert; Penner, Iris K; Noack, Thomas K; Zettl, Uwe K

    2016-03-01

    Multiple sclerosis (MS) is an immune mediated disease of the central nervous system (CNS) and the leading cause of non-traumatic disability among young and middle-aged adults in the western world. One of its most prevalent and debilitating symptoms is fatigue. Despite the general acceptance of the idea of an immune pathogenesis of MS itself, the role of autoimmunity in the course of MS-fatigue is a matter of debate. Both immune-related processes (acute inflammation, chronic inflammation, immune-mediated neurodegeneration, immune-mediated alterations of endocrine functions related to fatigue) and presumably non-immune-mediated disturbances and factors (sleep disturbances, depression, cognitive alterations, chronic infections, adverse effects of medications) contribute to the clinical picture. Data from in vitro and animal experiments has provided evidence for a role of cytokines as IL-1 and TNF-alpha. This association could not be verified directly in blood samples from humans whereas whole blood stimulation protocols gave some indirect evidence for a role of cytokines in MS-fatigue. MRI being able to detect acute and chronic immune mediated damage to the CNS could depict that global atrophy of gray or white matter does not correlate with fatigue. Rather, distinctive clusters of lesions and atrophy at different locations, mostly bifrontal or in subcortical structures, correlate specifically with fatigue. Regardless of the difficulties in pinpointing the immunogenesis of MS-fatigue, an important role of autoimmunity is strongly supported by an indirect route: A growing amount of data shows that the highly effective immunotherapeutics which have been introduced to MS-treatment over the last years effectively and sustainably stabilize and ameliorate fatigue in parallel to their dampening effects on the neuroinflammatory process. This review summarizes the existing data on the relation between inflammation, patterns of CNS-lesions and the effects of immunotherapeutics

  9. Genetic adaptation of the antibacterial human innate immunity network

    Lazarus Ross

    2011-07-01

    Full Text Available Abstract Background Pathogens have represented an important selective force during the adaptation of modern human populations to changing social and other environmental conditions. The evolution of the immune system has therefore been influenced by these pressures. Genomic scans have revealed that immune system is one of the functions enriched with genes under adaptive selection. Results Here, we describe how the innate immune system has responded to these challenges, through the analysis of resequencing data for 132 innate immunity genes in two human populations. Results are interpreted in the context of the functional and interaction networks defined by these genes. Nucleotide diversity is lower in the adaptors and modulators functional classes, and is negatively correlated with the centrality of the proteins within the interaction network. We also produced a list of candidate genes under positive or balancing selection in each population detected by neutrality tests and showed that some functional classes are preferential targets for selection. Conclusions We found evidence that the role of each gene in the network conditions the capacity to evolve or their evolvability: genes at the core of the network are more constrained, while adaptation mostly occurred at particular positions at the network edges. Interestingly, the functional classes containing most of the genes with signatures of balancing selection are involved in autoinflammatory and autoimmune diseases, suggesting a counterbalance between the beneficial and deleterious effects of the immune response.

  10. Cell walls of Saccharomyces cerevisiae differentially modulated innate immunity and glucose metabolism during late systemic inflammation.

    Bushansingh Baurhoo

    Full Text Available BACKGROUND: Salmonella causes acute systemic inflammation by using its virulence factors to invade the intestinal epithelium. But, prolonged inflammation may provoke severe body catabolism and immunological diseases. Salmonella has become more life-threatening due to emergence of multiple-antibiotic resistant strains. Mannose-rich oligosaccharides (MOS from cells walls of Saccharomyces cerevisiae have shown to bind mannose-specific lectin of Gram-negative bacteria including Salmonella, and prevent their adherence to intestinal epithelial cells. However, whether MOS may potentially mitigate systemic inflammation is not investigated yet. Moreover, molecular events underlying innate immune responses and metabolic activities during late inflammation, in presence or absence of MOS, are unknown. METHODS AND PRINCIPAL FINDINGS: Using a Salmonella LPS-induced systemic inflammation chicken model and microarray analysis, we investigated the effects of MOS and virginiamycin (VIRG, a sub-therapeutic antibiotic on innate immunity and glucose metabolism during late inflammation. Here, we demonstrate that MOS and VIRG modulated innate immunity and metabolic genes differently. Innate immune responses were principally mediated by intestinal IL-3, but not TNF-α, IL-1 or IL-6, whereas glucose mobilization occurred through intestinal gluconeogenesis only. MOS inherently induced IL-3 expression in control hosts. Consequent to LPS challenge, IL-3 induction in VIRG hosts but not differentially expressed in MOS hosts revealed that MOS counteracted LPS's detrimental inflammatory effects. Metabolic pathways are built to elucidate the mechanisms by which VIRG host's higher energy requirements were met: including gene up-regulations for intestinal gluconeogenesis (PEPCK and liver glycolysis (ENO2, and intriguingly liver fatty acid synthesis through ATP citrate synthase (CS down-regulation and ATP citrate lyase (ACLY and malic enzyme (ME up-regulations. However, MOS host

  11. Kicking off adaptive immunity: the discovery of dendritic cells

    Katsnelson, Alla

    2006-01-01

    In 1973, Ralph Steinman and Zanvil Cohn discovered an unusual looking population of cells with an unprecedented ability to activate naive T cells. Dubbed “dendritic cells,” these cells are now known as the primary instigators of adaptive immunity.

  12. Adaptive immunity to rhinoviruses: sex and age matter

    Pritchard Antonia L

    2010-12-01

    Full Text Available Abstract Background Rhinoviruses (RV are key triggers in acute asthma exacerbations. Previous studies suggest that men suffer from infectious diseases more frequently and with greater severity than women. Additionally, the immune response to most infections and vaccinations decreases with age. Most immune function studies do not account for such differences, therefore the aim of this study was to determine if the immune response to rhinovirus varies with sex or age. Methods Blood mononuclear cells were isolated from 63 healthy individuals and grouped by sex and age (≤50 years old and ≥52 years old. Cells were cultured with rhinovirus 16 at a multiplicity of infection of 1. The chemokine IP-10 was measured at 24 h as an index of innate immunity while IFNγ and IL-13 were measured at 5 days as an index of adaptive immunity. Results Rhinovirus induced IFNγ and IL-13 was significantly higher in ≤50 year old women than in age matched men (p 0.005. There was no sex or age based difference in rhinovirus induced IP-10 expression. Both IFNγ and IL-13 were negatively correlated with age in women but not in men. Conclusions This study suggests that pre-menopausal women have a stronger adaptive immune response to rhinovirus infection than men and older people, though the mechanisms responsible for these differences remain to be determined. Our findings highlight the importance of gender and age balance in clinical studies and in the development of new treatments and vaccines.

  13. Monocyte-derived dendritic cells in innate and adaptive immunity.

    León, Beatriz; Ardavín, Carlos

    2008-01-01

    Monocytes have been classically considered essential elements in relation with innate immune responses against pathogens, and inflammatory processes caused by external aggressions, infection and autoimmune disease. However, although their potential to differentiate into dendritic cells (DCs) was discovered 14 years ago, their functional relevance with regard to adaptive immune responses has only been uncovered very recently. Studies performed over the last years have revealed that monocyte-derived DCs play an important role in innate and adaptive immunity, due to their microbicidal potential, capacity to stimulate CD4(+) and CD8(+) T-cell responses and ability to regulate Immunoglobulin production by B cells. In addition, monocyte-derived DCs not only constitute a subset of DCs formed at inflammatory foci, as previously thought, but also comprise different subsets of DCs located in antigen capture areas, such as the skin and the intestinal, respiratory and reproductive tracts. PMID:18362945

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

    Kipnis, Jonathan

    2016-08-19

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

  15. Innate immunity and inflammation in ageing: a key for understanding age-related diseases

    Colonna-Romano Giuseppina

    2005-05-01

    Full Text Available Abstract The process of maintaining life for the individual is a constant struggle to preserve his/her integrity. This can come at a price when immunity is involved, namely systemic inflammation. Inflammation is not per se a negative phenomenon: it is the response of the immune system to the invasion of viruses or bacteria and other pathogens. During evolution the human organism was set to live 40 or 50 years; today, however, the immune system must remain active for much a longer time. This very long activity leads to a chronic inflammation that slowly but inexorably damages one or several organs: this is a typical phenomenon linked to ageing and it is considered the major risk factor for age-related chronic diseases. Alzheimer's disease, atherosclerosis, diabetes and even sarcopenia and cancer, just to mention a few – have an important inflammatory component, though disease progression seems also dependent on the genetic background of individuals. Emerging evidence suggests that pro-inflammatory genotypes are related to unsuccessful ageing, and, reciprocally, controlling inflammatory status may allow a better chance of successful ageing. In other words, age-related diseases are "the price we pay" for a life-long active immune system: this system has also the potential to harm us later, as its fine tuning becomes compromised. Our immune system has evolved to control pathogens, so pro-inflammatory responses are likely to be evolutionarily programmed to resist fatal infections with pathogens aggressively. Thus, inflammatory genotypes are an important and necessary part of the normal host responses to pathogens in early life, but the overproduction of inflammatory molecules might also cause immune-related inflammatory diseases and eventually death later. Therefore, low responder genotypes involved in regulation of innate defence mechanisms, might better control inflammatory responses and age-related disease development, resulting in an increased

  16. The Adaptive Immune System of Haloferax volcanii

    Lisa-Katharina Maier

    2015-02-01

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

  17. Metainflammation in Diabetic Coronary Artery Disease: Emerging Role of Innate and Adaptive Immune Responses.

    Aravindhan, Vivekanandhan; Madhumitha, Haridoss

    2016-01-01

    Globally, noncommunicable chronic diseases such as Type-2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD) are posing a major threat to the world. T2DM is known to potentiate CAD which had led to the coining of a new clinical entity named diabetic CAD (DM-CAD), leading to excessive morbidity and mortality. The synergistic interaction between these two comorbidities is through sterile inflammation which is now being addressed as metabolic inflammation or metainflammation, which plays a pivotal role during both early and late stages of T2DM and also serves as a link between T2DM and CAD. This review summarises the current concepts on the role played by both innate and adaptive immune responses in setting up metainflammation in DM-CAD. More specifically, the role played by innate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs), NOD1-like receptors (NLRs), Rig-1-like receptors (RLRs), and C-type lectin like receptors (CLRs) and metabolic endotoxemia in fuelling metainflammation in DM-CAD would be discussed. Further, the role played by adaptive immune cells (Th1, Th2, Th17, and Th9 cells) in fuelling metainflammation in DM-CAD will also be discussed. PMID:27610390

  18. Bile acids in regulation of inflammation and immunity: friend or foe?

    Zhu, Ci; Fuchs, Claudia D; Halilbasic, Emina; Trauner, Michael

    2016-01-01

    Apart from their pivotal role in dietary lipid absorption and cholesterol homeostasis, bile acids (BAs) are increasingly recognised as important signalling molecules in the regulation of systemic endocrine functions. As such BAs are natural ligands for several nuclear hormone receptors and G-protein-coupled receptors. Through activating various signalling pathways, BAs not only regulate their own synthesis, enterohepatic recirculation and metabolism, but also immune homeostasis. This makes BAs attractive therapeutic agents for managing metabolic and inflammatory liver disorders. Recent experimental and clinical evidence indicates that BAs exert beneficial effects in cholestatic and metabolically driven inflammatory diseases. This review elucidates how different BAs function as pathogenetic factors and potential therapeutic agents for inflammation-driven liver diseases, focusing on their role in regulation of inflammation and immunity. PMID:27586800

  19. Crosstalk between Adipocytes and Immune Cells in Adipose Tissue Inflammation and Metabolic Dysregulation in Obesity

    Huh, Jin Young; Park, Yoon Jeong; Ham, Mira; Kim, Jae Bum

    2014-01-01

    Recent findings, notably on adipokines and adipose tissue inflammation, have revised the concept of adipose tissues being a mere storage depot for body energy. Instead, adipose tissues are emerging as endocrine and immunologically active organs with multiple effects on the regulation of systemic energy homeostasis. Notably, compared with other metabolic organs such as liver and muscle, various inflammatory responses are dynamically regulated in adipose tissues and most of the immune cells in ...

  20. Bilateral regulatory action of corticotropin-releasing hormone on immune-mediated inflammation

    YANG Ce; JIANG Jian-xin

    2009-01-01

    @@ In trauma, infection and hemorrhagic shock derived stress, primary and secondary injury may result in severe derangement in the internal environment. The abnormal changes of immune-mediated inflammation interfere its pathogenesis and development directly. In recent years, various aspects of neuroendocrine responses, especially the regulatory effects of hypothalamic-pituitary-adrenal and sympathetico-adrenomedullary axes in inflammatory diseases have been the focus of research.

  1. Immunology and Homeopathy. 2. Cells of the Immune System and Inflammation

    Riccardo Ortolani; Francesco Pontarollo; Anita Conforti; Paolo Bellavite

    2006-01-01

    Here we describe the results of some experimental laboratory studies aimed at verifying the efficacy of high dilutions of substances and of homeopathic medicines in models of inflammation and immunity. Studies carried out on basophils, lymphocytes, granulocytes and fibroblasts are reviewed. This approach may help to test under controlled conditions the main principles of homeopathy such as ‘similarity’ of drug action at the cellular level and the effects of dilution/dynamization on the drug a...

  2. 5-Lipoxygenase Pathway, Dendritic Cells, and Adaptive Immunity

    Hedi Harizi

    2004-01-01

    Full Text Available 5-lipoxygenase (5-LO pathway is the major source of potent proinflammatory leukotrienes (LTs issued from the metabolism of arachidonic acid (AA, and best known for their roles in the pathogenesis of asthma. These lipid mediators are mainly released from myeloid cells and may act as physiological autocrine and paracrine signalling molecules, and play a central role in regulating the interaction between innate and adaptive immunity. The biological actions of LTs including their immunoregulatory and proinflammatory effects are mediated through extracellular specific G-protein-coupled receptors. Despite their role in inflammatory cells, such as neutrophils and macrophages, LTs may have important effects on dendritic cells (DC-mediated adaptive immunity. Several lines of evidence show that DC not only are important source of LTs, but also become targets of their actions by producing other lipid mediators and proinflammatory molecules. This review focuses on advances in 5-LO pathway biology, the production of LTs from DC and their role on various cells of immune system and in adaptive immunity.

  3. Influence of Asian dust particles on immune adjuvant effects and airway inflammation in asthma model mice.

    Jun Kurai

    Full Text Available An Asian dust storm (ADS contains airborne particles that affect conditions such as asthma, but the mechanism of exacerbation is unclear. The objective of this study was to compare immune adjuvant effects and airway inflammation induced by airborne particles collected on ADS days and the original ADS soil (CJ-1 soil in asthma model mice.Airborne particles were collected on ADS days in western Japan. NC/Nga mice were co-sensitized by intranasal instillation with ADS airborne particles and/or Dermatophagoides farinae (Df, and with CJ-1 soil and/or Df for 5 consecutive days. Df-sensitized mice were stimulated with Df challenge intranasally at 7 days after the last Df sensitization. At 24 hours after challenge, serum allergen specific antibody, differential leukocyte count and inflammatory cytokines in bronchoalveolar lavage fluid (BALF were measured, and airway inflammation was examined histopathologically.Co-sensitization with ADS airborne particles and Df increased the neutrophil and eosinophil counts in BALF. Augmentation of airway inflammation was also observed in peribronchiolar and perivascular lung areas. Df-specific serum IgE was significantly elevated by ADS airborne particles, but not by CJ-1 soil. Levels of interleukin (IL-5, IL-13, IL-6, and macrophage inflammatory protein-2 were higher in BALF in mice treated with ADS airborne particles.These results suggest that substances attached to ADS airborne particles that are not in the original ADS soil may play important roles in immune adjuvant effects and airway inflammation.

  4. Diverse Roles of Inhibitor of Differentiation 2 in Adaptive Immunity

    Lucille Rankin

    2011-01-01

    Full Text Available The helix-loop-helix (HLH transcription factor inhibitor of DNA binding 2 (Id2 has been implicated as a regulator of hematopoiesis and embryonic development. While its role in early lymphopoiesis has been well characterized, new roles in adaptive immune responses have recently been uncovered opening exciting new directions for investigation. In the innate immune system, Id2 is required for the development of mature natural killer (NK cells, lymphoid tissue-inducer (LTi cells, and the recently identified interleukin (IL-22 secreting nonconventional innate lymphocytes found in the gut. In addition, Id2 has been implicated in the development of specific dendritic cell (DC subsets, decisions determining the formation of αβ and γδ T-cell development, NK T-cell behaviour, and in the maintenance of effector and memory CD8+ T cells in peripheral tissues. Here, we review the current understanding of the role of Id2 in lymphopoiesis and in the development of the adaptive immune response required for maintaining immune homeostasis and immune protection.

  5. Human neutrophil elastase inhibitors in innate and adaptive immunity.

    Fitch, P M; Roghanian, A; Howie, S E M; Sallenave, J-M

    2006-04-01

    Recent evidence shows that human neutrophil elastase inhibitors can be synthesized locally at mucosal sites. In addition to efficiently targeting bacterial and host enzymes, they can be released in the interstitium and in the lumen of mucosa, where they have been shown to have antimicrobial activities, and to activate innate immune responses. This review will address more particularly the pleiotropic functions of low-molecular-mass neutrophil elastase inhibitors [SLPI (secretory leucocyte proteinase inhibitor) and elafin] and, more specifically, their role in the development of the adaptive immune response. PMID:16545094

  6. Viral Diversity Threshold for Adaptive Immunity in Prokaryotes

    Ariel D Weinberger; Wolf, Yuri I.; Lobkovsky, Alexander E; Gilmore, Michael S.; Eugene V Koonin

    2012-01-01

    ABSTRACT Bacteria and archaea face continual onslaughts of rapidly diversifying viruses and plasmids. Many prokaryotes maintain adaptive immune systems known as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated genes (Cas). CRISPR-Cas systems are genomic sensors that serially acquire viral and plasmid DNA fragments (spacers) that are utilized to target and cleave matching viral and plasmid DNA in subsequent genomic invasions, offering critical immunologi...

  7. Was the evolutionary road towards adaptive immunity paved with endothelium?

    van Niekerk, Gustav; Davis, Tanja; Engelbrecht, Anna-Mart

    2015-01-01

    Background The characterization of a completely novel adaptive immune system (AIS) in jawless vertebrates (hagfish and lampreys) presents an excellent opportunity for exploring similarities and differences in design principles. It also highlights a somewhat neglected question: Why did vertebrates, representing only 5 % of all animals, evolve a system as complex as an AIS twice, whereas invertebrates failed to do so? A number of theories have been presented in answer to this question. However,...

  8. Immune-inflammatory responses in atherosclerosis: Role of an adaptive immunity mainly driven by T and B cells.

    Chistiakov, Dimitry A; Orekhov, Alexander N; Bobryshev, Yuri V

    2016-09-01

    Adaptive immune response plays an important role in atherogenesis. In atherosclerosis, the proinflammatory immune response driven by Th1 is predominant but the anti-inflammatory response mediated mainly by regulatory T cells is also present. The role of Th2 and Th17 cells in atherogenesis is still debated. In the plaque, other T helper cells can be observed such as Th9 and Th22 but is little is known about their impact in atherosclerosis. Heterogeneity of CD4(+) T cell subsets presented in the plaque may suggest for plasticity of T cell that can switch the phenotype dependening on the local microenvironment and activating/blocking stimuli. Effector T cells are able to recognize self-antigens released by necrotic and apoptotic vascular cells and induce a humoral immune reaction. Tth cells resided in the germinal centers help B cells to switch the antibody class to the production of high-affinity antibodies. Humoral immunity is mediated by B cells that release antigen-specific antibodies. A variety of B cell subsets were found in human and murine atherosclerotic plaques. In mice, B1 cells could spontaneously produce atheroprotective natural IgM antibodies. Conventional B2 lymphocytes secrete either proatherogenic IgG, IgA, and IgE or atheroprotective IgG and IgM antibodies reactive with oxidation-specific epitopes on atherosclerosis-associated antigens. A small population of innate response activator (IRA) B cells, which is phenotypically intermediate between B1 and B2 cells, produces IgM but possesses proatherosclerotic properties. Finally, there is a minor subset of splenic regulatory B cells (Bregs) that protect against atherosclerotic inflammation through support of generation of Tregs and production of anti-inflammatory cytokines IL-10 and TGF-β and proapoptotic molecules. PMID:27262513

  9. Activation of the reward system boosts innate and adaptive immunity.

    Ben-Shaanan, Tamar L; Azulay-Debby, Hilla; Dubovik, Tania; Starosvetsky, Elina; Korin, Ben; Schiller, Maya; Green, Nathaniel L; Admon, Yasmin; Hakim, Fahed; Shen-Orr, Shai S; Rolls, Asya

    2016-08-01

    Positive expectations contribute to the clinical benefits of the placebo effect. Such positive expectations are mediated by the brain's reward system; however, it remains unknown whether and how reward system activation affects the body's physiology and, specifically, immunity. Here we show that activation of the ventral tegmental area (VTA), a key component of the reward system, strengthens immunological host defense. We used 'designer receptors exclusively activated by designer drugs' (DREADDs) to directly activate dopaminergic neurons in the mouse VTA and characterized the subsequent immune response after exposure to bacteria (Escherichia coli), using time-of-flight mass cytometry (CyTOF) and functional assays. We found an increase in innate and adaptive immune responses that were manifested by enhanced antibacterial activity of monocytes and macrophages, reduced in vivo bacterial load and a heightened T cell response in the mouse model of delayed-type hypersensitivity. By chemically ablating the sympathetic nervous system (SNS), we showed that the reward system's effects on immunity are, at least partly, mediated by the SNS. Thus, our findings establish a causal relationship between the activity of the VTA and the immune response to bacterial infection. PMID:27376577

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

    Sun, Jun; Deem, Michael

    2006-03-01

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

  11. Human primary adipocytes exhibit immune cell function: adipocytes prime inflammation independent of macrophages.

    Kees Meijer

    Full Text Available BACKGROUND: Obesity promotes inflammation in adipose tissue (AT and this is implicated in pathophysiological complications such as insulin resistance, type 2 diabetes and cardiovascular disease. Although based on the classical hypothesis, necrotic AT adipocytes (ATA in obese state activate AT macrophages (ATM that then lead to a sustained chronic inflammation in AT, the link between human adipocytes and the source of inflammation in AT has not been in-depth and systematically studied. So we decided as a new hypothesis to investigate human primary adipocytes alone to see whether they are able to prime inflammation in AT. METHODS AND RESULTS: Using mRNA expression, human preadipocytes and adipocytes express the cytokines/chemokines and their receptors, MHC II molecule genes and 14 acute phase reactants including C-reactive protein. Using multiplex ELISA revealed the expression of 50 cytokine/chemokine proteins by human adipocytes. Upon lipopolysaccharide stimulation, most of these adipocyte-associated cytokines/chemokines and immune cell modulating receptors were up-regulated and a few down-regulated such as (ICAM-1, VCAM-1, MCP-1, IP-10, IL-6, IL-8, TNF-α and TNF-β highly up-regulated and IL-2, IL-7, IL-10, IL-13 and VEGF down-regulated. In migration assay, human adipocyte-derived chemokines attracted significantly more CD4+ T cells than controls and the number of migrated CD4+ cells was doubled after treating the adipocytes with LPS. Neutralizing MCP-1 effect produced by adipocytes reduced CD4+ migration by approximately 30%. CONCLUSION: Human adipocytes express many cytokines/chemokines that are biologically functional. They are able to induce inflammation and activate CD4+ cells independent of macrophages. This suggests that the primary event in the sequence leading to chronic inflammation in AT is metabolic dysfunction in adipocytes, followed by production of immunological mediators by these adipocytes, which is then exacerbated by

  12. IP-10-mediated T cell homing promotes cerebral inflammation over splenic immunity to malaria infection.

    Catherine Q Nie

    2009-04-01

    Full Text Available Plasmodium falciparum malaria causes 660 million clinical cases with over 2 million deaths each year. Acquired host immunity limits the clinical impact of malaria infection and provides protection against parasite replication. Experimental evidence indicates that cell-mediated immune responses also result in detrimental inflammation and contribute to severe disease induction. In both humans and mice, the spleen is a crucial organ involved in blood stage malaria clearance, while organ-specific disease appears to be associated with sequestration of parasitized erythrocytes in vascular beds and subsequent recruitment of inflammatory leukocytes. Using a rodent model of cerebral malaria, we have previously found that the majority of T lymphocytes in intravascular infiltrates of cerebral malaria-affected mice express the chemokine receptor CXCR3. Here we investigated the effect of IP-10 blockade in the development of experimental cerebral malaria and the induction of splenic anti-parasite immunity. We found that specific neutralization of IP-10 over the course of infection and genetic deletion of this chemokine in knockout mice reduces cerebral intravascular inflammation and is sufficient to protect P. berghei ANKA-infected mice from fatality. Furthermore, our results demonstrate that lack of IP-10 during infection significantly reduces peripheral parasitemia. The increased resistance to infection observed in the absence of IP-10-mediated cell trafficking was associated with retention and subsequent expansion of parasite-specific T cells in spleens of infected animals, which appears to be advantageous for the control of parasite burden. Thus, our results demonstrate that modulating homing of cellular immune responses to malaria is critical for reaching a balance between protective immunity and immunopathogenesis.

  13. From Lipid Retention to Immune-Mediate Inflammation and Associated Angiogenesis in the Pathogenesis of Atherosclerosis.

    Usman, Ammara; Ribatti, Domenico; Sadat, Umar; Gillard, Jonathan H

    2015-08-26

    Atherosclerosis is a leading cause of mortality and long-term morbidity worldwide. It is a lipoprotein-driven disease that leads to plaque formation at focal areas in the arterial blood vessels through intimal inflammation, necrosis, fibrosis, and calcification. Adventitial and intimal angiogenesis contributes to the progression of intimal hyperplasia and the development of a necrotic core. The volatile nature of an atheromatous plaque is responsible for approximately 60% of symptomatic carotid artery diseases and about 75% of acute coronary events. In this review the pathogenesis of atherosclerosis is discussed from the initial step of lipid retention to advanced stages of immune-mediate inflammation and associated angiogenesis. Mechanisms of plaque rupture are also discussed. PMID:26156748

  14. Inhibitors of apoptosis (IAPs) regulate intestinal immunity and inflammatory bowel disease (IBD) inflammation

    Pedersen, Jannie; LaCasse, Eric C; Seidelin, Jakob B;

    2014-01-01

    -linked lymphoproliferative disease type 2 (XLP2), in which 20% of patients develop severe intestinal inflammation. In addition, 4% of males with early-onset IBD also have inactivating mutations in XIAP. Therefore, the IAPs play a greater role in gut homeostasis, immunity and IBD development than previously suspected, and...... (NOD)1/NOD2 and other intracellular NOD-like receptors in response to bacterial pathogens. These pathways are important to the pathogenesis and treatment of inflammatory bowel disease (IBD). Inactivating mutations in the X-chromosome-linked IAP (XIAP) gene causes an immunodeficiency syndrome, X...

  15. Immune adaptive Gaussian mixture par ticle filter for state estimation

    Wenlong Huang; Xiaodan Wang; Yi Wang; Guohong Li

    2015-01-01

    The particle filter (PF) is a flexible and powerful sequen-tial Monte Carlo (SMC) technique capable of modeling nonlinear, non-Gaussian, and nonstationary dynamical systems. However, the generic PF suffers from particle degeneracy and sample im-poverishment, which greatly affects its performance for nonlinear, non-Gaussian tracking problems. To deal with those issues, an improved PF is proposed. The algorithm consists of a PF that uses an immune adaptive Gaussian mixture model (IAGM) based immune algorithm to re-approximate the posterior density. At the same time, three immune antibody operators are embed in the new filter. Instead of using a resample strategy, the newest obser-vation and conditional likelihood are integrated into those immune antibody operators to update the particles, which can further im-prove the diversity of particles, and drive particles toward their close local maximum of the posterior probability. The improved PF algorithm can produce a closed-form expression for the posterior state distribution. Simulation results show the proposed algorithm can maintain the effectiveness and diversity of particles and avoid sample impoverishment, and its performance is superior to several PFs and Kalman filters.

  16. Policing of gut microbiota by the adaptive immune system.

    Dollé, Laurent; Tran, Hao Q; Etienne-Mesmin, Lucie; Chassaing, Benoit

    2016-01-01

    The intestinal microbiota is a large and diverse microbial community that inhabits the intestine, containing about 100 trillion bacteria of 500-1000 distinct species that, collectively, provide benefits to the host. The human gut microbiota composition is determined by a myriad of factors, among them genetic and environmental, including diet and medication. The microbiota contributes to nutrient absorption and maturation of the immune system. As reciprocity, the host immune system plays a central role in shaping the composition and localization of the intestinal microbiota. Secretory immunoglobulins A (sIgAs), component of the adaptive immune system, are important player in the protection of epithelium, and are known to have an important impact on the regulation of microbiota composition. A recent study published in Immunity by Fransen and colleagues aimed to mechanistically decipher the interrelationship between sIgA and microbiota diversity/composition. This commentary will discuss these important new findings, as well as how future therapies can ultimately benefit from such discovery. PMID:26867587

  17. Dynamics of adaptive immunity against phage in bacterial populations

    Bradde, Serena; Tesileanu, Tiberiu; Balasubramanian, Vijay

    2015-01-01

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

  18. In vivo MR imaging of immune cell behavior and inflammation in mice using iron oxide particles. President award proceedings

    Interstitial immune cells, such as macrophage and dendritic cells, may migrate toward lymphatic tissues to deliver and manage immune information. However, little is known of the mechanisms that underlie their migration and action over the entire body. Iron oxide particles are commonly used as contrast agents in magnetic resonance (MR) imaging. The particles disturb the homogeneous magnetic field and generate dark spots on MR imaging that reveal where they are harbored by phagocytic immune cells. Contrast-enhanced MR lymphography with iron oxide particles is in the spotlight for visualizing lymphatic structures and the migration of immune cells in vivo. We previously demonstrated the potential of micron-sized particles of iron oxide (MPIOs) to reveal the migration of phagocytes with MR imaging noninvasively, without ex vivo cell labeling. Within an inflammatory condition, immune cells would behave differently from in a normal environment. In our current study, we evaluated the efficacy of cellular tracking in subcutaneous tissue with and without inflammation. In control mice, we observed areas of hypointensity at 48 or 60 hours after administration of MPIOs. In contrast, lipopolysaccharide (LPS)-induced inflammation accelerated the delivery of particles in the popliteal lymph node and showed different spatiotemporal distribution of areas of hypointensity, and their differing contrasts reflect the cell activity in the inflammatory environment. Heretofore individual differences in immune cell behavior in the presence of inflammation may have prevented investigation in vivo, high-resolution MR lymphography allows the noninvasive assessment of immune cell behavior and pathological conditions related to inflammation. (author)

  19. Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection.

    Hsu, Denise C; Sereti, Irini

    2016-04-01

    In the antiretroviral therapy (ART) era, serious non-AIDS events (SNAEs) have become the major causes of morbidity and mortality in HIV-infected persons. Early ART initiation has the strongest evidence for reducing SNAEs and mortality. Biomarkers of immune activation, inflammation and coagulopathy do not fully normalize despite virologic suppression and persistent immune activation is an important contributor to SNAEs. A number of strategies aimed to reduce persistent immune activation including ART intensification to reduce residual viremia; treatment of co-infections to reduce chronic antigen stimulation; the use of anti-inflammatory agents, reducing microbial translocation as well as interventions to improve immune recovery through cytokine administration and reducing lymphoid tissue fibrosis, have been investigated. To date, there is little conclusive evidence on which strategies beyond treatment of hepatitis B and C co-infections and reducing cardiovascular risk factors will result in clinical benefits in patients already on ART with viral suppression. The use of statins seems to show early promise and larger clinical trials are underway to confirm their efficacy. At this stage, clinical care of HIV-infected patients should therefore focus on early diagnosis and prompt ART initiation, treatment of active co-infections and the aggressive management of co-morbidities until further data are available. PMID:26915027

  20. Ascorbic acid: its role in immune system and chronic inflammation diseases.

    Sorice, Angela; Guerriero, Eliana; Capone, Francesca; Colonna, Giovanni; Castello, Giuseppe; Costantini, Susan

    2014-05-01

    Ascorbic acid (AA), also known as vitamin C, was initially identified as the factor preventing the scurvy disease, and became very popular for its antioxidant properties. It is an important co-substrate of a large class of enzymes, and regulates gene expression by interacting with important transcription factors. AA is important in all stressful conditions that are linked to inflammatory processes and involve immunity. It has been known for decades that the persistence of an inflammatory stimulus is responsible for the onset of many diseases. AA is essential to stimulate the immune system by increasing the strength and protection of the organism. Therefore, its immunostimulant, antinflammatory, antiviral and antibacterial roles are well known, we have summarized its main functions in different types of diseases related to the immune system and chronic inflammation. We can conclude that AA, due to its effects and diversity of regulated pathways, is suitable for use in various fields of medicine including immunology, toxicology, radiobiology and others. AA is not preferable to be used as an isolated mode of treatment, but it can be co-applied as an adjuvant to regulate immunity, gene expression and other important physiological processes. However, we propose that future studies will take into consideration the research of new combinations of antioxidant natural substances and drugs. PMID:24766384

  1. Anaphylatoxins coordinate innate and adaptive immune responses in allergic asthma.

    Schmudde, Inken; Laumonnier, Yves; Köhl, Jörg

    2013-02-01

    Allergic asthma is a chronic disease of the airways in which maladaptive Th2 and Th17 immune responses drive airway hyperresponsiveness (AHR), eosinophilic and neutrophilic airway inflammation and mucus overproduction. Airway epithelial and pulmonary vascular endothelial cells in concert with different resident and monocyte-derived dendritic cells (DC) play critical roles in allergen sensing and consecutive activation of TH cells and their differentiation toward TH2 and TH17 effector or regulatory T cells (Treg). Further, myeloid-derived regulatory cells (MDRC) act on TH cells and either suppress or enhance their activation. The complement-derived anaphylatoxins (AT) C3a and C5a are generated during initial antigen encounter and regulate the development of maladaptive immunity at allergen sensitization. Here, we will review the complex role of ATs in activation and modulation of different DC populations, MDRCs and CD4⁺ TH cells. We will also discuss the potential impact of ATs on the regulation of the pulmonary stromal compartment as an important means to regulate DC functions. PMID:23694705

  2. Risk factors that may modify the innate and adaptive immune responses in periodontal diseases.

    Knight, Ellie T; Liu, Jenny; Seymour, Gregory J; Faggion, Clovis M; Cullinan, Mary P

    2016-06-01

    Plaque-induced periodontal diseases occur in response to the accumulation of dental plaque. Disease manifestation and progression is determined by the nature of the immune response to the bacterial complexes in plaque. In general, predisposing factors for these periodontal diseases can be defined as those factors which retain or hinder the removal of plaque and, depending upon the nature of the immune response to this plaque, the disease will either remain stable and not progress or it may progress and result in chronic periodontitis. In contrast, modifying factors can be defined as those factors that alter the nature or course of the inflammatory lesion. These factors do not cause the disease but rather modify the chronic inflammatory response, which, in turn, is determined by the nature of the innate and adaptive immune responses and the local cytokine and inflammatory mediator networks. Chronic inflammation is characterized by vascular, cellular and repair responses within the tissues. This paper will focus on how common modifying factors, such as smoking, stress, hormonal changes, diabetes, metabolic syndrome and HIV/AIDS, influence each of these responses, together with treatment implications. As treatment planning in periodontics requires an understanding of the etiology and pathogenesis of the disease, it is important for all modifying factors to be taken into account. For some of these, such as smoking, stress and diabetic control, supportive health behavior advice within the dental setting should be an integral component for overall patient management. PMID:27045429

  3. Control of Dichotomic Innate and Adaptive Immune Responses by Artery Tertiary Lymphoid Organs in Atherosclerosis

    Falk eWeih

    2012-07-01

    Full Text Available Tertiary lymphoid organs (TLOs emerge in tissues in response to nonresolving inflammation such as chronic infection, graft rejection, and autoimmune disease. We identified artery TLOs (ATLOs in the adventitia adjacent to atherosclerotic plaques of aged hyperlipidemic ApoE-/- mice. ATLOs are structured into T cell areas harboring conventional dendritic cells (cDCs and monocyte-derived DCs (mDCs; B cell follicles containing follicular dendritic cells (FDCs within activated germinal centers; and peripheral niches of plasma cells. ATLOs also show extensive neoangiogenesis, aberrant lymphangiogenesis, and high endothelial venule (HEV neogenesis. Newly formed conduit networks connect the external lamina of the artery with HEVs in T cell areas. ATLOs recruit and generate lymphocyte subsets with opposing activities including activated CD4+ and CD8+ effector T cells, natural and induced CD4+ T regulatory cells (nTregs; iTregs as well as B-1 and B-2 cells at different stages of differentiation. These data indicate that ATLOs organize dichotomic innate and adaptive immune responses in atherosclerosis. In this review we discuss the novel concept that dichotomic immune responses towards atherosclerosis-specific antigens are carried out by ATLOs in the adventitia of the arterial wall and that malfunction of the tolerogenic arm of ATLO immunity triggers transition from silent autoimmune reactivity to clinically overt disease.

  4. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation.

    Izcue, Ana; Coombes, Janine L; Powrie, Fiona

    2006-08-01

    The gastrointestinal (GI) tract is the main interface where the body encounters exogenous antigens. It is crucial that the local response here is tightly regulated to avoid an immune reaction against dietary antigens and commensal flora while still mounting an efficient defense against pathogens. Faults in establishing intestinal tolerance can lead to disease, inducing local and often also systemic inflammation. Studies in human as well as in animal models suggest a role for regulatory T cells (Tregs) in maintaining intestinal homeostasis. Transfer of Tregs can not only prevent the development of colitis in animal models but also cure established disease, acting both systemically and at the site of inflammation. In this review, we discuss the major regulatory pathways, including transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), and their role in Treg-mediated control of systemic and mucosal responses. In addition, we give an overview of the known mechanisms of lymphocyte migration to the intestine and discuss how CD103 expression can influence the balance between regulatory and effector T cells. Further understanding of the factors that control the activity of Tregs in different immune compartments may facilitate the design of strategies to target regulation in a tissue-specific way. PMID:16903919

  5. The pentraxins PTX3 and SAP in innate immunity, regulation of inflammation and tissue remodelling.

    Bottazzi, Barbara; Inforzato, Antonio; Messa, Massimo; Barbagallo, Marialuisa; Magrini, Elena; Garlanda, Cecilia; Mantovani, Alberto

    2016-06-01

    Pentraxins are a superfamily of fluid phase pattern recognition molecules conserved in evolution and characterized by a cyclic multimeric structure. C-reactive protein (CRP) and serum amyloid P component (SAP) constitute the short pentraxin arm of the superfamily. CRP and SAP are produced in the liver in response to IL-6 and are acute phase reactants in humans and mice respectively. In addition SAP has been shown to affect tissue remodelling and fibrosis by stabilizing all types of amyloid fibrils and by regulating monocyte to fibrocyte differentiation. Pentraxin 3 (PTX3) is the prototype of the long pentraxin arm. Gene targeted mice and genetic and epigenetic studies in humans suggest that PTX3 plays essential non-redundant roles in innate immunity and inflammation as well as in tissue remodelling. Recent studies have revealed the role of PTX3 as extrinsic oncosuppressor, able to tune cancer-related inflammation. In addition, at acidic pH PTX3 can interact with provisional matrix components promoting inflammatory matrix remodelling. Thus acidification during tissue repair sets PTX3 in a tissue remodelling and repair mode, suggesting that matrix and microbial recognition are common, ancestral features of the humoral arm of innate immunity. PMID:26921689

  6. Immune modulatory effects of IL-22 on allergen-induced pulmonary inflammation.

    Ping Fang

    Full Text Available IL-22 is a Th17/Th22 cytokine that is increased in asthma. However, recent animal studies showed controversial findings in the effects of IL-22 in allergic asthma. To determine the role of IL-22 in ovalbumin-induced allergic inflammation we generated inducible lung-specific IL-22 transgenic mice. Transgenic IL-22 expression and signaling activity in the lung were determined. Ovalbumin (OVA-induced pulmonary inflammation, immune responses, and airway hyperresponsiveness (AHR were examined and compared between IL-22 transgenic mice and wild type controls. Following doxycycline (Dox induction, IL-22 protein was readily detected in the large (CC10 promoter and small (SPC promoter airway epithelial cells. IL-22 signaling was evidenced by phosphorylated STAT3. After OVA sensitization and challenge, compared to wild type littermates, IL-22 transgenic mice showed decreased eosinophils in the bronchoalveolar lavage (BAL, and in lung tissue, decreased mucus metaplasia in the airways, and reduced AHR. Among the cytokines and chemokines examined, IL-13 levels were reduced in the BAL fluid as well as in lymphocytes from local draining lymph nodes of IL-22 transgenic mice. No effect was seen on the levels of serum total or OVA-specific IgE or IgG. These findings indicate that IL-22 has immune modulatory effects on pulmonary inflammatory responses in allergen-induced asthma.

  7. Complement Activation Pathways: A Bridge between Innate and Adaptive Immune Responses in Asthma

    Wills-Karp, Marsha

    2007-01-01

    Although it is widely accepted that allergic asthma is driven by T helper type 2 (Th2)-polarized immune responses to innocuous environmental allergens, the mechanisms driving these aberrant immune responses remain elusive. Recent recognition of the importance of innate immune pathways in regulating adaptive immune responses have fueled investigation into the role of innate immune pathways in the pathogenesis of asthma. The phylogenetically ancient innate immune system, the complement system, ...

  8. Caspase recruitment domain-containing protein 9 signaling in innate immunity and inflammation.

    Roth, Susanne; Ruland, Jürgen

    2013-06-01

    Caspase recruitment domain-containing protein (Card)9 is a nonredundant adapter protein that functions in the innate immune system in the assembly of multifunctional signaling complexes. Together with B cell lymphoma (Bcl)10 and the paracaspase, mucosa-associated lymphoid tissue lymphoma translocation protein (Malt)1, Card9 links spleen-tyrosine kinase (Syk)-coupled C-type lectin receptors to inflammatory responses. Card9 signaling also responds to intracellular danger sensors, such as retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs) and nucleotide-oligomerization domain (Nod)2. Card9 complexes are engaged upon fungal, bacterial, or viral recognition, and they are essential for host protection. Moreover, Card9 polymorphisms are commonly associated with human inflammatory diseases. Here, we discuss the molecular regulation and the physiological functions of Card9 in host defense and immune homeostasis, and provide a framework for the therapeutic targeting of Card9 signaling in immune-mediated diseases. PMID:23523010

  9. Immune dysregulation mediated by the oral microbiome: potential link to chronic inflammation and atherosclerosis.

    Slocum, C; Kramer, C; Genco, C A

    2016-07-01

    Cardiovascular disease is an inflammatory disorder characterized by the progressive formation of plaque in coronary arteries, termed atherosclerosis. It is a multifactorial disease that is one of the leading causes of death worldwide. Although a number of risk factors have been associated with disease progression, the underlying inflammatory mechanisms contributing to atherosclerosis remain to be fully delineated. Within the last decade, the potential role for infection in inflammatory plaque progression has received considerable interest. Microbial pathogens associated with periodontal disease have been of particular interest due to the high levels of bacteremia that are observed after routine dental procedures and every day oral activities, such as tooth brushing. Here, we explore the potential mechanisms that may explain how periodontal pathogens either directly or indirectly elicit immune dysregulation and consequently progressive inflammation manifested as atherosclerosis. Periodontal pathogens have been shown to contribute directly to atherosclerosis by disrupting endothelial cell function, one of the earliest indicators of cardiovascular disease. Oral infection is thought to indirectly induce elevated production of inflammatory mediators in the systemic circulation. Recently, a number of studies have been conducted focusing on how disruption of the gut microbiome influences the systemic production of proinflammatory cytokines and consequently exacerbation of inflammatory diseases such as atherosclerosis. It is clear that the immune mechanisms leading to atherosclerotic plaque progression, by oral infection, are complex. Understanding the immune pathways leading to disease progression is essential for the future development of anti-inflammatory therapies for this chronic disease. PMID:26791914

  10. HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression

    Frincke James M

    2010-10-01

    Full Text Available Abstract Background 17α-Ethynyl-5-androsten-3β, 7β, 17β-triol (HE3286 is a synthetic derivative of an endogenous steroid androstenetriol (β-AET, a metabolite of the abundant adrenal steroid deyhdroepiandrosterone (DHEA, with broad anti-inflammatory activities. We tested the ability of this novel synthetic steroid with improved pharmacological properties to limit non-productive lung inflammation in rodents and attempted to gauge its immunological impact. Methods and Results In mice, oral treatment with HE3286 (40 mg/kg significantly (p in vivo (ovalbumin immunization. When mice treated for two weeks with HE3286 were challenged with K. pneumoniae, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups. Conclusions HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of β-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.

  11. Regulation of apoptosis and innate immune stimuli in inflammation-induced preterm labor.

    Jaiswal, Mukesh K; Agrawal, Varkha; Mallers, Timothy; Gilman-Sachs, Alice; Hirsch, Emmet; Beaman, Kenneth D

    2013-12-01

    An innate immune response is required for successful implantation and placentation. This is regulated, in part, by the a2 isoform of V-ATPase (a2V) and the concurrent infiltration of M1 (inflammatory) and M2 (anti-inflammatory) macrophages to the uterus and placenta. The objective of the present study was to identify the role of a2V during inflammation-induced preterm labor in mice and its relationship to the regulation of apoptosis and innate immune responses. Using a mouse model of infection-induced preterm delivery, gestational tissues were collected 8 h after intrauterine inoculation on day 14.5 of pregnancy with either saline or peptidoglycan (PGN; a TLR 2 agonist) and polyinosinic-polycytidylic acid [poly(I:C); a TLR3 agonist], modeling Gram-positive bacterial and viral infections, respectively. Expression of a2V decreased significantly in the placenta, uterus, and fetal membranes during PGN+poly(I:C)-induced preterm labor. Expression of inducible NO synthase was significantly upregulated in PGN+poly(I:C)-treated placenta and uterus. PGN+poly(I:C) treatment disturbed adherens junction proteins and increased apoptotic cell death via an extrinsic pathway of apoptosis among uterine decidual cells and spongiotrophoblasts. F4/80(+) macrophages were increased and polarization was skewed in PGN+poly(I:C)-treated uterus toward double-positive CD11c(+) (M1) and CD206(+) (M2) cells, which are critical for the clearance of dying cells and rapid resolution of inflammation. Expression of Nlrp3 and activation of caspase-1 were increased in PGN+poly(I:C)-treated uterus, which could induce pyroptosis. These results suggest that the double hit of PGN+poly(I:C) induces preterm labor via reduction of a2V expression and simultaneous activation of apoptosis and inflammatory processes. PMID:24163412

  12. Tinospora cordifolia inhibits autoimmune arthritis by regulating key immune mediators of inflammation and bone damage.

    Sannegowda, K M; Venkatesha, S H; Moudgil, K D

    2015-12-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints leading to tissue damage. Despite the availability of potent drugs including the biologics, many patients fail to respond to them, whereas others suffer adverse effects following long-term use of these drugs. Accordingly, the use of natural herbal products by RA patients has been increasing over the years. However, limited information about the mechanism of action of these natural products is a major shortcoming that prevents the widespread acceptance of herbal therapy by professionals and patients alike. In this study, we demonstrated the anti-arthritic activity of Tinospora cordifolia extract (TCE) using the rat adjuvant-induced arthritis model of human RA and elaborated the immune mechanisms underlying this effect. TCE treatment suppressed arthritic inflammation and bone and cartilage damage. The anti-inflammatory effect of TCE was mediated via reduction of the pro-inflammatory cytokines such as: IL-1β, TNF-α, IL-6, and IL-17; the frequency of IL-17-producing T cells; and the production of chemokines such as RANTES. Furthermore, TCE treatment limited bone damage by shifting the balance of mediators of bone remodeling (e.g., receptor activator of nuclear factor-kB ligand [RANKL] and MMP-9) in favor of anti-osteoclastic activity. Our results suggest that TCE and its bioactive components should be evaluated for their utility as therapeutic adjuncts to conventional drugs against RA. PMID:26467057

  13. Dynamics of adaptive immunity against phage in bacterial populations

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

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

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

    Yingru eLiu

    2011-03-01

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

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

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

    2011-01-01

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

  16. Trained immunity: A program of innate immune memory in health and disease.

    Netea, Mihai G; Joosten, Leo A B; Latz, Eicke; Mills, Kingston H G; Natoli, Gioacchino; Stunnenberg, Hendrik G; O'Neill, Luke A J; Xavier, Ramnik J

    2016-04-22

    The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity, as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed "trained immunity" or "innate immune memory." Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, new therapeutic strategies for the treatment of immune deficiency states, and modulation of exaggerated inflammation in autoinflammatory diseases. PMID:27102489

  17. Hidden talents of natural killers: NK cells in innate and adaptive immunity

    Cooper, Megan A.; Colonna, Marco; Yokoyama, Wayne M.

    2009-01-01

    Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells and producing immunoregulatory cytokines. Herein, we discuss recent studies that indicate that NK cells span the conventional boundaries between innate and adaptive immunity. For example, it was recently discovered that NK cells have the capacity for memory-like responses, a property that was previously thought to be limited to adaptive immunity. NK cells have also been identified in multiple tissues, and ...

  18. Two separate mechanisms of enforced viral replication balance innate and adaptive immune activation.

    Shaabani, Namir; Khairnar, Vishal; Duhan, Vikas; Zhou, Fan; Tur, Rita Ferrer; Häussinger, Dieter; Recher, Mike; Tumanov, Alexei V; Hardt, Cornelia; Pinschewer, Daniel; Christen, Urs; Lang, Philipp A; Honke, Nadine; Lang, Karl S

    2016-02-01

    The induction of innate and adaptive immunity is essential for controlling viral infections. Limited or overwhelming innate immunity can negatively impair the adaptive immune response. Therefore, balancing innate immunity separately from activating the adaptive immune response would result in a better antiviral immune response. Recently, we demonstrated that Usp18-dependent replication of virus in secondary lymphatic organs contributes to activation of the innate and adaptive immune responses. Whether specific mechanisms can balance innate and adaptive immunity separately remains unknown. In this study, using lymphocytic choriomeningitis virus (LCMV) and replication-deficient single-cycle LCMV vectors, we found that viral replication of the initial inoculum is essential for activating virus-specific CD8(+) T cells. In contrast, extracellular distribution of virus along the splenic conduits is necessary for inducing systemic levels of type I interferon (IFN-I). Although enforced virus replication is driven primarily by Usp18, B cell-derived lymphotoxin beta contributes to the extracellular distribution of virus along the splenic conduits. Therefore, lymphotoxin beta regulates IFN-I induction independently of CD8(+) T-cell activity. We found that two separate mechanisms act together in the spleen to guarantee amplification of virus during infection, thereby balancing the activation of the innate and adaptive immune system. PMID:26553386

  19. The colitis-associated transcriptional profile of commensal Bacteroides thetaiotaomicron enhances adaptive immune responses to a bacterial antigen.

    Jonathan J Hansen

    Full Text Available BACKGROUND: Inflammatory bowel diseases (IBD may be caused in part by aberrant immune responses to commensal intestinal microbes including the well-characterized anaerobic gut commensal Bacteroides thetaiotaomicron (B. theta. Healthy, germ-free HLA-B27 transgenic (Tg rats develop chronic colitis when colonized with complex gut commensal bacteria whereas non-transgenic (nTg rats remain disease-free. However, the role of B. theta in causing disease in Tg rats is unknown nor is much known about how gut microbes respond to host inflammation. METHODS: Tg and nTg rats were monoassociated with a human isolate of B. theta. Colonic inflammation was assessed by histologic scoring and tissue pro-inflammatory cytokine measurement. Whole genome transcriptional profiling of B. theta recovered from ceca was performed using custom GeneChips and data analyzed using dChip, Significance Analysis of Microarrays, and Gene Set Enrichment Analysis (GSEA software. Western Blots were used to determine adaptive immune responses to a differentially expressed B. theta gene. RESULTS: B. theta monoassociated Tg rats, but not nTg or germ-free controls, developed chronic colitis. Transcriptional profiles of cecal B. theta were significantly different in Tg vs. nTg rats. GSEA revealed that genes in KEGG canonical pathways involved in bacterial growth and metabolism were downregulated in B. theta from Tg rats with colitis though luminal bacterial concentrations were unaffected. Bacterial genes in the Gene Ontology molecular function "receptor activity", most of which encode nutrient binding proteins, were significantly upregulated in B. theta from Tg rats and include a SusC homolog that induces adaptive immune responses in Tg rats. CONCLUSIONS: B. theta induces colitis in HLA-B27 Tg rats, which is associated with regulation of bacterial genes in metabolic and nutrient binding pathways that may affect host immune responses. These studies of the host-microbial dialogue may lead to

  20. Distinct immune signatures in the colon of Crohn's disease and ankylosing spondylitis patients in the absence of inflammation.

    Dunn, Elliott T J; Taylor, Edward S; Stebbings, Simon; Schultz, Michael; Butt, A Grant; Kemp, Roslyn A

    2016-05-01

    Crohn's disease (CD) is an inflammatory bowel disease characterized by patchy inflammation of the gastrointestinal tract. Ankylosing spondylitis (AS) is primarily characterized by inflammation of the lower vertebral column, and many patients with AS present with inflammatory gut symptoms. Genome-wide association studies have highlighted significant overlap in short nucleotide polymorphisms for both diseases. We hypothesized that patients with CD and AS have a common intestinal immune signature, characterized by inflammatory T cells, compared with healthy people. We designed a pilot study to determine both the feasibility of defining complex immune signatures from primary tissue, and differences in the local immune signature of people with inflammatory diseases compared with healthy people. Intestinal biopsies were obtained by colonoscopy from healthy patients, non-inflamed regions of CD patients and AS patients with inflammatory gut symptoms. A flow cytometry platform was developed measuring polyfunctional T-cell populations based on cytokines, surface molecules and transcription factors. There was overlap in the immune signature of people with CD or AS, characterized by changes in the frequency of regulatory T cells, compared with healthy people. There were significant differences in frequencies of other polyfunctional T-cell populations-CD patients had an increased frequency of T cells producing interleukin-22 (IL-22) and interferon-γ, whereas AS patients had an increased frequency of T cells producing IL-2; compared with healthy people. These data indicate that the local immune signature could be described in these patients and that distinct immune mechanisms may underlie disease progression. PMID:26647966

  1. Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I.

    Omar Khalid

    Full Text Available Cardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease.Gene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry.Gene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold and protein overexpression (1.3 to 1.62-fold was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice.Overexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for which clusterin

  2. Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I

    Gordts, Philip L.; Ellinwood, N. Matthew; Schwartz, Philip H.; Dickson, Patricia I.; Esko, Jeffrey D.; Wang, Raymond Y.

    2016-01-01

    Background Cardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease. Methods Gene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry. Results Gene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice. Conclusions Overexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for

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

    Zu Yun-Xiao; Zhou Jie

    2012-01-01

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

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

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

  5. Clinical Application of Development of Nonantibiotic Macrolides That Correct Inflammation-Driven Immune Dysfunction in Inflammatory Skin Diseases

    Alberto Molares-Vila; Elena Sanchez-Blanco; Carmen Rodriguez-Cerdeira

    2012-01-01

    Background. Inflammation-driven immune dysfunction supports the development of several chronic human disorders including skin diseases. Nonantibiotic macrolides have anti-inflammatory and/or immunomodulatory activity that suggests the exploitation of these in the treatment of skin diseases characterized by inflammatory disorders. Materials and Methods. We performed an extensive review of the nonantibiotic macrolide literature published between 2005 and 2012, including cross-references of any ...

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

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

    2016-05-18

    Methods to monitor and manipulate the immune system are of enormous clinical interest. For example, the development of vaccines represents one of the earliest and greatest accomplishments of the biomedical research enterprise. More recently, drugs capable of "reawakening" the immune system to cancer have generated enormous excitement. But, much remains to be done. All drugs available today that manipulate the immune system cannot distinguish between "good" and "bad" immune responses and thus drive general and systemic immune suppression or activation. Indeed, with the notable exception of vaccines, our ability to monitor and manipulate antigen-specific immune responses is in its infancy. Achieving this finer level of control would be highly desirable. For example, it might allow the pharmacological editing of pathogenic immune responses without restricting the ability of the immune system to defend against infection. On the diagnostic side, a method to comprehensively monitor the circulating, antigen-specific antibody population could provide a treasure trove of clinically useful biomarkers, since many diseases expose the immune system to characteristic molecules that are deemed foreign and elicit the production of antibodies against them. This Perspective will discuss the state-of-the-art of this area with a focus on what we consider seminal opportunities for the chemistry community to contribute to this important field. PMID:27115249

  7. The hedgehog receptor patched1 in T cells is dispensable for adaptive immunity in mice.

    Kai D Michel

    Full Text Available Hedgehog (Hh signaling modulates T cell development and function but its exact role remains a matter of debate. To further address this issue we made use of conditional knock-out mice in which the Hh receptor Patched1 (Ptch is inactivated in the T cell lineage. Thymocyte development was moderately compromised by the deletion of Ptch as characterized by reduced numbers of CD4 and CD8 single-positive cells. In contrast, peripheral T cells were not affected. Proliferation and IFNγ secretion by Ptch-deficient T cells were indistinguishable from controls irrespectively of whether we used strong or suboptimal conditions for stimulation. Analysis of CTL and Treg cell functions did not reveal any differences between both genotypes, and T cell apoptosis induced by glucocorticoids or γ-irradiation was also similar. Surprisingly, absence of Ptch did not lead to an activation of canonic Hh signaling in peripheral T cells as indicated by unaltered expression levels of Gli1 and Gli2. To test whether we could uncover any role of Ptch in T cells in vivo we subjected the mutant mice to three different disease models, namely allogeneic bone marrow transplantation mimicking graft-versus-host disease, allergic airway inflammation as a model of asthma and growth of adoptively transferred melanoma cells as a means to test tumor surveillance by the immune system. Nonetheless, we were neither able to demonstrate any difference in the disease courses nor in any pathogenic parameter in these three models of adaptive immunity. We therefore conclude that the Hh receptor Ptch is dispensable for T cell function in vitro as well as in vivo.

  8. Oral immune therapy: targeting the systemic immune system via the gut immune system for the treatment of inflammatory bowel disease

    Ilan, Yaron

    2016-01-01

    Inflammatory bowel diseases (IBD) are associated with an altered systemic immune response leading to inflammation-mediated damage to the gut and other organs. Oral immune therapy is a method of systemic immune modulation via alteration of the gut immune system. It uses the inherit ability of the innate system of the gut to redirect the systemic innate and adaptive immune responses. Oral immune therapy is an attractive clinical approach to treat autoimmune and inflammatory disorders. It can in...

  9. Evolutionary Dynamics of the Prokaryotic Adaptive Immunity System CRISPR-Cas in an Explicit Ecological Context

    Iranzo, Jaime; Lobkovsky, Alexander E; Wolf, Yuri I; Koonin, Eugene V

    2013-01-01

    A stochastic, agent-based mathematical model of the coevolution of the archaeal and bacterial adaptive immunity system, CRISPR-Cas, and lytic viruses shows that CRISPR-Cas immunity can stabilize the virus-host coexistence rather than leading to the extinction of the virus. In the model, CRISPR-Cas immunity does not specifically promote viral diversity, presumably because the selection pressure on each single proto-spacer is too weak. However, the overall virus diversity in the presence of CRI...

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

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

    2016-01-01

    There are notable inter-individual variations in vaccine-specific antibody responses in vaccinated children. The aim of our study was to investigate whether early-life environmental factors and adaptive immune maturation prior and close to measles–mumps–rubella (MMR) immunization relate to magnitudes of vaccine-specific antibody titers. In the FARMFLORA birth cohort, including both farming and non-farming families, children were immunized with the MMR vaccine at 18 months of age. MMR vaccine-...

  11. Biogenesis pathways of RNA guides in archaeal and bacterial CRISPR-Cas adaptive immunity

    Charpentier, Emmanuelle; Richter, Hagen; Oost, van der John; White, Malcolm F.

    2015-01-01

    CRISPR-Cas is an RNA-mediated adaptive immune system that defends bacteria and archaea against mobile genetic elements. Short mature CRISPR RNAs (crRNAs) are key elements in the interference step of the immune pathway. A CRISPR array composed of a series of repeats interspaced by spacer sequences

  12. Senescence of the adaptive immune system in health and aging-associated autoimmune disease

    van der Geest, Kornelis Stephan Mario

    2015-01-01

    Aging of the immune system may contribute to the development of aging-associated autoimmune diseases, such as giant cell arteritis, polymyalgia rheumatica and rheumatoid arthritis. The aim of this thesis was to identify aging-dependent changes of the adaptive immune system that promote autoimmunity

  13. Chemokines, innate and adaptive immunity, and respiratory disease

    Sabroe, I.; Lloyd, C.M.; Whyte, M K B; Dower, S.K.; Williams, T J; Pease, J.E.

    2002-01-01

    Selective leukocyte trafficking and recruitment is primarily regulated by a specific family of small proteins called “chemokines”. This extended family shepherds and guides leukocytes through their lives, facilitating their development, regulating their interactions with other leukocyte types, and guiding their recruitment to sites of inflammation.

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

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

    2016-03-01

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

  15. Nanoparticles for nasal delivery of vaccines : monitoring adaptive immune responses

    Keijzer, C.

    2013-01-01

    The continuous emergence of new pathogens and growing drug resistance of microorganisms asks for innovative vaccination strategies. An alternative to conventional multiple injection vaccines is the nasal route of vaccine delivery. The immune response induced following nasal antigen delivery depends

  16. Host adaptive immunity deficiency in severe pandemic influenza

    Bermejo-Martin, Jesus F; Martin-Loeches, Ignacio; Rello, Jordi; Antón, Andres; Almansa, Raquel; Xu, Luoling; Lopez-Campos, Guillermo; Pumarola, Tomás; Ran, Longsi; Ramirez, Paula; Banner, David; Cheuk Ng, Derek; Socias, Lorenzo; Loza, Ana; Andaluz, David

    2010-01-01

    Introduction Pandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown. Methods We utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analy...

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

    LI Fengling; ZHANG Shicui; WANG Zhiping; LI Hongyan

    2011-01-01

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

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

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

    2011-03-01

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

  19. Immunoglobulin M: restrainer of inflammation and mediator of immune evasion by Plasmodium falciparum malaria

    Pleass, Richard J; Moore, Shona C; Stevenson, Liz;

    2016-01-01

    Immunoglobulin M (IgM) is an ancient antibody class that is found in all vertebrates, with the exception of coelacanths, and is indispensable in both innate and adaptive immunity. The equally ancient human malaria parasite, Plasmodium falciparum, formed an intimate relationship with IgM with which...

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

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

    2016-01-01

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

  1. Caloric Restriction reduces inflammation and improves T cell-mediated immune response in obese mice but concomitant consumption of curcumin/piperine adds no further benefit

    Obesity is associated with low-grade inflammation and impaired immune response. Caloric restriction (CR) has been shown to inhibit inflammatory response and enhance cell-mediated immune function. Curcumin, the bioactive phenolic component of turmeric spice, is proposed to have anti-obesity and anti-...

  2. Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non obese humans

    Calorie restriction (CR) inhibits inflammation and slows aging in many animal species, but in rodents housed in pathogen-free facilities, CR impairs immunity against certain pathogens. However, little is known about the effects of long-term moderate CR on immune function in humans. In this multi-cen...

  3. The microbiota in adaptive immune homeostasis and disease.

    Honda, Kenya; Littman, Dan R

    2016-07-01

    In the mucosa, the immune system's T cells and B cells have position-specific phenotypes and functions that are influenced by the microbiota. These cells play pivotal parts in the maintenance of immune homeostasis by suppressing responses to harmless antigens and by enforcing the integrity of the barrier functions of the gut mucosa. Imbalances in the gut microbiota, known as dysbiosis, can trigger several immune disorders through the activity of T cells that are both near to and distant from the site of their induction. Elucidation of the mechanisms that distinguish between homeostatic and pathogenic microbiota-host interactions could identify therapeutic targets for preventing or modulating inflammatory diseases and for boosting the efficacy of cancer immunotherapy. PMID:27383982

  4. Dynamic expression of leukocyte innate immune genes in whole blood from horses with lipopolysaccharide-induced acute systemic inflammation

    Vinther, Anne Mette L.; Skovgaard, Kerstin; Heegaard, Peter M. H.;

    2015-01-01

    Background: In horses, insights into the innate immune processes in acute systemic inflammation are limited even though these processes may be highly important for future diagnostic and therapeutic advances in high-mortality disease conditions as the systemic inflammatory response syndrome (SIRS...... were compared with baseline levels. Results: Systemic inflammation was confirmed by the presence of clinical and hematological changes which were consistent with SIRS. The clinical response to LPS was transient and brief as all horses except one showed unaltered general demeanor after 24 h. Twenty......-two leukocyte genes were significantly regulated at at least one time point during the experimental period. By close inspection of the temporal responses the dynamic changes in mRNA abundance revealed a very rapid onset of both pro-and anti-inflammatory mediators and a substantial variation in both expression...

  5. Comparison of Watermelon and Carbohydrate Beverage on Exercise-Induced Alterations in Systemic Inflammation, Immune Dysfunction, and Plasma Antioxidant Capacity

    R. Andrew Shanely

    2016-08-01

    Full Text Available Consuming carbohydrate- and antioxidant-rich fruits during exercise as a means of supporting and enhancing both performance and health is of interest to endurance athletes. Watermelon (WM contains carbohydrate, lycopene, l-citrulline, and l-arginine. WM may support exercise performance, augment antioxidant capacity, and act as a countermeasure to exercise-induced inflammation and innate immune changes. Trained cyclists (n = 20, 48 ± 2 years participated in a randomized, placebo controlled, crossover study. Subjects completed two 75 km cycling time trials after either 2 weeks ingestion of 980 mL/day WM puree or no treatment. Subjects drank either WM puree containing 0.2 gm/kg carbohydrate or a 6% carbohydrate beverage every 15 min during the time trials. Blood samples were taken pre-study and pre-, post-, 1 h post-exercise. WM ingestion versus no treatment for 2-weeks increased plasma l-citrulline and l-arginine concentrations (p < 0.0125. Exercise performance did not differ between WM puree or carbohydrate beverage trials (p > 0.05, however, the rating of perceived exertion was greater during the WM trial (p > 0.05. WM puree versus carbohydrate beverage resulted in a similar pattern of increase in blood glucose, and greater increases in post-exercise plasma antioxidant capacity, l-citrulline, l-arginine, and total nitrate (all p < 0.05, but without differences in systemic markers of inflammation or innate immune function. Daily WM puree consumption fully supported the energy demands of exercise, and increased post-exercise blood levels of WM nutritional components (l-citrulline and l-arginine, antioxidant capacity, and total nitrate, but without an influence on post-exercise inflammation and changes in innate immune function.

  6. The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance

    Chmelař, Jindřich; Chung, K.-J.; Chavakis, T.

    2013-01-01

    Roč. 109, č. 3 (2013), s. 399-406. ISSN 0340-6245 Institutional support: RVO:60077344 Keywords : Obesity * adipose tissue * inflammation * review * leukocytes Subject RIV: EC - Immunology Impact factor: 5.760, year: 2013

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

    van Niekerk, Gustav; Engelbrecht, Anna-Mart

    2015-04-01

    Jawless vertebrates utilize a form of adaptive immunity that is functionally based on molecular effectors that are completely different from those of vertebrates. This observation raises an intriguing question: why did vertebrates, representing only 5% of all animals, twice evolve a system as complex as adaptive immunity? Theories aimed at identifying a selective pressure that would 'drive' the development of an adaptive immune system (AIS) fail to explain why invertebrates would not similarly develop an AIS. We argue that an AIS can only be implemented in a certain physiological context, i.e., that an AIS represents an unevolvable trait for invertebrates. The immune system is functionally integrated with other systems; therefore a preexisting physiological innovation unique to vertebrates may have acted as the prerequisite infrastructure that allowed the development of an AIS. We propose that future efforts should be directed toward identifying the evolutionary release that allowed the development of an adaptive immune system in vertebrates. In particular, the advent of specialized adipocytes might have expanded the metabolic scope of vertebrates, allowing the opportunistic incorporation of an AIS. However, physiological innovations, unique to (or more developed in) vertebrates, support the implementation of an AIS. Thus, understanding the interaction between systems (e.g. neural-immune-adipose connection) may illuminate our understanding regarding the perplexing immunological dimorphism within the animal kingdom. PMID:25698354

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

    Arnold Isabelle C

    2011-11-01

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

  9. Uncomplicated Diverticular Disease: Innate and Adaptive Immunity in Human Gut Mucosa before and after Rifaximin

    Rossella Cianci; Simona Frosali; Danilo Pagliari; Paola Cesaro; Lucio Petruzziello; Fabio Casciano; Raffaele Landolfi; Guido Costamagna; Franco Pandolfi

    2014-01-01

    Background/Aim. Uncomplicated diverticular disease (UDD) is a frequent condition in adults. The pathogenesis of symptoms remains unknown. Bacteria are able to interact with Toll-like receptors (TLRs) and to induce inflammation through both innate immunity and T-cell recruitment. We investigated the pattern of TLRs 2 and 4 and the intestinal homing in patients with UDD before and after a course of Rifaximin. Methods. Forty consecutive patients with UDD and 20 healthy asymptomatic subjects were...

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

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

    2014-01-01

    Bacteria and archaea have evolved an adaptive, heritable immune system that recognizes and protects against viruses or plasmids. This system, known as the CRISPR-Cas system, allows the host to recognize and incorporate short foreign DNA or RNA sequences, called ‘spacers’ into its CRISPR system. Spacers in the CRISPR system provide a record of the history of bacteria and phage coevolution. We use a physical model to study the dynamics of this coevolution as it evolves stochastically over time....

  11. Integrating Innate and Adaptive Immunity for Intrusion Detection

    Tedesco, Gianni; Aickelin, Uwe

    2010-01-01

    Network Intrusion Detection Systems (NDIS) monitor a network with the aim of discerning malicious from benign activity on that network. While a wide range of approaches have met varying levels of success, most IDS's rely on having access to a database of known attack signatures which are written by security experts. Nowadays, in order to solve problems with false positive alters, correlation algorithms are used to add additional structure to sequences of IDS alerts. However, such techniques are of no help in discovering novel attacks or variations of known attacks, something the human immune system (HIS) is capable of doing in its own specialised domain. This paper presents a novel immune algorithm for application to an intrusion detection problem. The goal is to discover packets containing novel variations of attacks covered by an existing signature base.

  12. The placenta in toxicology. Part II: Systemic and local immune adaptations in pregnancy.

    Svensson-Arvelund, Judit; Ernerudh, Jan; Buse, Eberhard; Cline, J Mark; Haeger, Jan-Dirk; Dixon, Darlene; Markert, Udo R; Pfarrer, Christiane; De Vos, Paul; Faas, Marijke M

    2014-01-01

    During pregnancy, the maternal immune system is challenged by the semiallogeneic fetus, which must be tolerated without compromising fetal or maternal health. This review updates the systemic and local immune changes taking place during human pregnancy, including some examples in rodents. Systemic changes are induced by contact of maternal blood with placental factors and include enhanced innate immunity with increased activation of granulocytes and nonclassical monocytes. Although a bias toward T helper (Th2) and regulatory T cell (Treg) immunity has been associated with healthy pregnancy, the relationship between different circulating Th cell subsets is not straightforward. Instead, these adaptations appear most evidently at the fetal-maternal interface, where for instance Tregs are enriched and promote fetal tolerance. Also innate immune cells, that is, natural killer cells and macrophages, are enriched, constituting the majority of decidual leukocytes. These cells not only contribute to immune regulation but also aid in establishing the placenta by promoting trophoblast recruitment and angiogenesis. Thus, proper interaction between leukocytes and placental trophoblasts is necessary for normal placentation and immune adaptation. Consequently, spontaneous maladaptation or interference of the immune system with toxic substances may be important contributing factors for the development of pregnancy complications such as preeclampsia, preterm labor, and recurrent miscarriages. PMID:23531796

  13. Evidence of the adaptive evolution of immune genes in chicken

    Cormican Paul; Downing Tim; O'Farrelly Cliona; Bradley Daniel G; Lloyd Andrew T

    2009-01-01

    Abstract The basis for understanding the characteristics of gene functional categories in chicken has been enhanced by the ongoing sequencing of the zebra finch genome, the second bird species to be extensively sequenced. This sequence provides an avian context for examining how variation in chicken has evolved since its divergence from its common ancestor with zebra finch as well as well as a calibrating point for studying intraspecific diversity within chicken. Immune genes have been subjec...

  14. CRISPR-Cas adaptive immune systems of the sulfolobales

    Garrett, Roger Antony; Shah, Shiraz Ali; Erdmann, Susanne;

    2015-01-01

    The Sulfolobales have provided good model organisms for studying CRISPR-Cas systems of the crenarchaeal kingdom of the archaea. These organisms are infected by a wide range of exceptional archaea-specific viruses and conjugative plasmids, and their CRISPR-Cas systems generally exhibit extensive...... structural and functional diversity. They carry large and multiple CRISPR loci and often multiple copies of diverse Type I and Type III interference modules as well as more homogeneous adaptation modules. These acidothermophilic organisms have recently provided seminal insights into both the adaptation...... process, the diverse modes of interference, and their modes of regulation. The functions of the adaptation and interference modules tend to be loosely coupled and the stringency of the crRNA-DNA sequence matching during DNA interference is relatively low, in contrast to some more streamlined CRISPR...

  15. Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation

    Cao, Z.; Conway, K.L.; Heath, R.J.; Rush, J.S.; Leshchiner, E.S.; Ramirez-Ortiz, Z.G.; Nedelsky, N.B.; Huang, H.; Ng, A.; Gardet, A.; Cheng, S.C.; Shamji, A.F.; Rioux, J.D.; Wijmenga, C.; Netea, M.G.; Means, T.K.; Daly, M.J.; Xavier, R.J.

    2015-01-01

    CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigatin

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

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

    2015-01-01

    Extensive research has been carried out to decipher the function of the adaptive immune response in atherosclerosis, with the expectation that it will pave the road for the design of immunomodulatory therapies that will prevent or reverse the progression of the disease. All this work has led to the concept that some T- and B-cell subsets are proatherogenic, whereas others are atheroprotective. In addition to the immune response occurring in the spleen and lymph nodes, it has been shown that l...

  17. Immune system adaptations during competition period in female cross-country skiers

    Stenholm, Johanna

    2011-01-01

    Stenholm, Johanna. Immune system adaptations during competition period in female cross-country skiers. Master’s Thesis in Exercise Physiology, Department of Biology of Physical Activity. University of Jyväskylä. 95pp. Purpose. This study was undertaken to characterize the extent of immune and endocrine changes in competition period and related to two competition weekends in well trained athletes in different parts of the competition period. An additional purpose was to evaluate if the cha...

  18. Innate and adaptive immunity at Mucosal Surfaces of the Female Reproductive Tract: Stratification and Integration of Immune Protection against the Transmission of Sexually Transmitted Infections

    Hickey, DK; Patel, MV; Fahey, JV; Wira, CR

    2011-01-01

    This review examines the multiple levels of pre-existing immunity in the upper and lower female reproductive tract. In addition, we highlight the need for further research of innate and adaptive immune protection of mucosal surfaces in the female reproductive tract. Innate mechanisms include the mucus lining, a tight epithelial barrier and the secretion of antimicrobial peptides and cytokines by epithelial and innate immune cells. Stimulation of the innate immune system also serves to bridge ...

  19. Blockade of Wnt/β-Catenin Pathway Aggravated Silica-Induced Lung Inflammation through Tregs Regulation on Th Immune Responses

    Wujing Dai

    2016-01-01

    Full Text Available CD4+ T cells play an important role in regulating silica-induced inflammation and fibrosis. Recent studies showed that Wnt/β-catenin pathway could modulate the function and the differentiation of CD4+ T cells. Therefore, Wnt/β-catenin pathway may participate in the development and progress of silicosis. To investigate the role of Wnt/β-catenin pathway, we used lentivirus expressing β-catenin shRNA to block the Wnt/β-catenin pathway by intratracheal instillation to the mice model of silicosis. Treatment of lentivirus could significantly aggravate the silica-induced lung inflammation and attenuated the fibrosis at the late stage. By analyzing CD4+ T cells, we found that blockade of Wnt/β-catenin pathway suppressed regulatory T cells (Tregs. Reciprocally, enhanced Th17 response was responsible for the further accumulation of neutrophils and production of proinflammatory cytokines. In addition, blockade of Wnt/β-catenin pathway delayed the Th1/Th2 polarization by inhibiting Tregs and Th2 response. These results indicated that Wnt/β-catenin pathway could regulate Tregs to modulate Th immune response, which finally altered the pathological character of silicosis. Our study suggested that Wnt/β-catenin pathway might be a potential target to treat the silica-induced inflammation and fibrosis.

  20. Innate lymphoid cell function in the context of adaptive immunity.

    Bando, Jennifer K; Colonna, Marco

    2016-06-21

    Innate lymphoid cells (ILCs) are a family of innate immune cells that have diverse functions during homeostasis and disease. Subsets of ILCs have phenotypes that mirror those of polarized helper T cell subsets in their expression of core transcription factors and effector cytokines. Given the similarities between these two classes of lymphocytes, it is important to understand which functions of ILCs are specialized and which are redundant with those of T cells. Here we discuss genetic mouse models that have been used to delineate the contributions of ILCs versus those of T cells and review the current understanding of the specialized in vivo functions of ILCs. PMID:27328008

  1. GATA-3 Function in Innate and Adaptive Immunity.

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

    2014-01-01

    : The zinc-finger transcription factor GATA-3 has received much attention as a master regulator of T helper 2 (Th2) cell differentiation, during which it controls interleukin-4 (IL-4), IL-5, and IL-13 expression. More recently, GATA-3 was shown to contribute to type 2 immunity through regulation of group 2 innate lymphoid cell (ILC2) development and function. Furthermore, during thymopoiesis, GATA-3 represses B cell potential in early T cell precursors, activates TCR signaling in pre-T cells,...

  2. Adaptive immune-genetic algorithm for global optimization to multivariable function

    2007-01-01

    An adaptive immune-genetic algorithm(AIGA)is proposed to avoid premature convergence and guarantee the diversity of the population.Rapid immune response (secondary response),adaptive mutation and density operators in the AIGA are emphatically designed to improve the searching ability,greatly increase the converging speed,and decrease locating the local maxima due to the premature convergence.The simulation results obtained from the global optimization to four multivariable and multi-extreme functions show that AIGA converges rapidly,guarantees the diversity,stability and good searching ability.

  3. DMPD: ITAM-based signaling beyond the adaptive immune response. [Dynamic Macrophage Pathway CSML Database

    Full Text Available AM-based signaling beyond the adaptive immune response. PubmedID 16332394 Title ITAM-based signaling beyond...16332394 ITAM-based signaling beyond the adaptive immune response. Fodor S, Jakus Z..., Mocsai A. Immunol Lett. 2006 Apr 15;104(1-2):29-37. Epub 2005 Nov 28. (.png) (.svg) (.html) (.csml) Show IT...e (.html) CSML File (.csml) Open .csml file with CIOPlayer Open .csml file with CIOPlayer - ※CIO Playerのご利用上の注意 Open .csml file with CIO Open .csml file with CIO - ※CIOのご利用上の注意 ...

  4. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: innate immune responses in plants.

    Schulze-Lefert, P

    2010-04-01

    Plants rely exclusively upon mechanisms of innate immunity. Current concepts of the plant innate immune system are based largely on two forms of immunity that engage distinct classes of immune receptors. These receptors enable the recognition of non-self structures that are either conserved between members of a microbial class or specific to individual strains of a microbe. One type of receptor comprises membrane-resident pattern recognition receptors (PRRs) that detect widely conserved microbe-associated molecular patterns (MAMPs) on the cell surface. A second type of mainly intracellular immune sensors, designated resistance (R) proteins, recognizes either the structure or function of strain-specific pathogen effectors that are delivered inside host cells. Phytopathogenic microorganisms have evolved a repertoire of effectors, some of which are delivered into plant cells to sabotage MAMP-triggered immune responses. Plants appear to have also evolved receptors that sense cellular injury by the release and perception of endogenous damage-associated molecular patterns (DAMPs). It is possible that the integration of MAMP and DAMP responses is critical to mount robust MAMP-triggered immunity. This signal integration might help to explain why plants are colonized in nature by remarkably diverse and seemingly asymptomatic microbial communities. PMID:20415853

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

    Sandra Winning

    2016-01-01

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

  6. Size does not matter: commensal microorganisms forge tumor-promoting inflammation and anti-tumor immunity

    Rutkowski, Melanie R.; Conejo-Garcia, Jose R.

    2015-01-01

    Recent studies have demonstrated that the commensal microbiota are indispensable for the maintenance of immune homeostasis, orchestration of immune responses against pathogens and most recently during cancer immunotherapy and malignant progression of extraintestinal tumors. Here we discuss the recent findings that a common genetic variation in TLR5 influences the progression and outcome of ovarian, sarcoma, and luminal breast tumors and the implications of these findings in light of recent publications describing the role of the commensal microbiota in control of the systemic immune system. PMID:25897427

  7. A New Method for Fastening the Convergence of Immune Algorithms Using an Adaptive Mutation Approach

    Ahmad F. Al-Ajlouni; Nabil Sabor; Sabah M. Ahmed; Mohammed Abo-Zahhad

    2012-01-01

    This paper presents a new adaptive mutation approach for fastening the convergence of immune algorithms (IAs). This method is adopted to realize the twin goals of maintaining diversity in the population and sustaining the convergence capacity of the IA. In this method, the mutation rate (pm) is adaptively varied depending on the fitness values of the solutions. Solutions of high fitness are protected, while solutions with sub-average fitness are total...

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

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

    2016-04-01

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

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

    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. PMID:10692124

  10. MiR-146 and miR-125 in the regulation of innate immunity and inflammation.

    Lee, Hye-Mi; Kim, Tae Sung; Jo, Eun-Kyeong

    2016-06-01

    Innate immune responses are primary, relatively limited, and specific responses to numerous pathogens and toxic molecules. Protein expression involved in these innate responses must be tightly regulated at both transcriptional level and post-transcriptional level to avoid the development of excessive inflammation that can be potentially harmful to the host. MicroRNAs are small noncoding RNAs (~22 nucleotides [nts]) that participate in the regulation of numerous physiological responses by targeting specific messenger RNAs to suppress their translation. Recent work has shown that several negative regulators of transcription including microRNAs play important roles in inhibiting the exacerbation of inflammatory responses and in the maintenance of immunological homeostasis. This emerging research area will provide new insights on how microRNAs regulate innate immune signaling. It might show that dysregulation of microRNA synthesis is associated with the pathogenesis of inflammatory and infectious diseases. In this review, we focused on miR-146 and miR-125 and described the roles these miRNAs in modulating innate immune signaling. These microRNAs can control inflammatory responses and the outcomes of pathogenic infections. [BMB Reports 2016; 49(6): 311-318]. PMID:26996343

  11. New directions in inflammation and immunity: the multi-functional role of the extracellular RNA/RNase system.

    Deindl, Elisabeth; Fischer, Silvia; Preissner, Klaus T

    2009-12-01

    In the mid-eighties of the last century, extracellular-proteolipid complexes have been identified in tumor patients and circulating RNA was suggested to represent a specific secretory product of cancer cells. The presence of specific types of RNA in a variety of cancer types proved to be useful in cancer diagnosis. It has been suggested that extracellular RNA and DNA are not inert molecules, but contain biological activities. Recent data have demonstrated that extracellular RNA is likely to present the up to now undefined "natural foreign surface", serving as an initiating factor in blood coagulation in vivo. Yet, extracellular RNA seems to have even more functions. Investigations on blood-brain-barrier have shown that extracellular RNA mediates endothelial permeability. Ample success has been achieved in administrating RNase in different animal models of vascular diseases, thereby significantly delaying thrombus formation and reducing cerebral edema formation with neuroprotection in acute stroke models. Furthermore, extracellular mammalian RNA was found to decrease tumor yield in a murine model system, suggesting that extracellular RNA might trigger immune response. Finally, extracellular nucleic acids were identified as danger signals involved in innate immunity related to neutrophil-mediated bacterial killing and haemocyte activation and coagulation in the insects. Thus, a new area of research on extracellular RNA functions with promising future perspectives just started in the field of inflammation and immunity. PMID:20361709

  12. Tactics used by HIV-1 to evade host innate, adaptive, and intrinsic immunities

    LU Lu; YU Fei; DU Lan-ying; XU Wei; JIANG Shi-bo

    2013-01-01

    Objective To review the mechanisms by which HIV evades different components of the host immune system.Data sources This review is based on data obtained from published articles from 1991 to 2012.To perform the PubMed literature search,the following key words were input:HIV and immune evasion.Study selection Articles containing information related to HIV immune evasion were selected.Results Although HIV is able to induce vigorous antiviral immune responses,viral replication cannot be fully controlled,and neither pre-existing infected cells nor latent HIV infection can be completely eradicated.Like many other enveloped viruses,HIV can escape recognition by the innate and adaptive immune systems.Recent findings have demonstrated that HIV can also successfully evade host restriction factors,the components of intrinsic immune system,such as APOBEC3G (apolipoprotein B mRNA-editing enzyme,catalytic polypeptide-like 3G),TRIM5α (tripartite motif 5-α),tetherin,and SAMHD1 (SAM-domain HD-domain containing protein).Conclusions HIV immune evasion plays an important role in HIV pathcgenesis.Fully understanding the tactics deployed by HIV to evade various components of the host immune systems will allow for the development of novel strategies aimed toward the prevention and cure of HIV/AIDS.

  13. The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity

    Damgaard, Rune Busk; Nachbur, Ueli; Yabal, Monica;

    2012-01-01

    -linked lymphoproliferative syndrome type-2 (XLP-2). Here, we demonstrate that the RING domain of XIAP is essential for NOD2 signaling and that XIAP contributes to exacerbation of inflammation-induced hepatitis in experimental mice. We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly...... signaling. We conclude that XIAP and LUBAC constitute essential ubiquitin ligases in NOD2-mediated inflammatory signaling and propose that deregulation of NOD2 signaling contributes to XLP-2 pathogenesis....

  14. Innate immunity is a key factor for the resolution of inflammation in asthma

    Barnig, Cindy; Levy, Bruce D.

    2015-01-01

    The resolution of inflammation is an integral and natural part of the physiological response to tissue injury, infection and allergens or other noxious stimuli. Resolution is now recognised as an active process with highly regulated cellular and biochemical events. Recent discoveries have highlighted that innate inflammatory cells have bimodal effector functions during the inflammatory response, including active roles during the resolution process. Several mediators displaying potent pro-reso...

  15. Adaptive and innate immune reactions regulating mast cell activation: from receptor-mediated signaling to responses

    Tkaczyk, Christine; Jensen, Bettina M; Iwaki, Shoko; Gilfillan, Alasdair M

    2006-01-01

    In this article, we have described studies that have demonstrated that mast cells can be activated as a consequence of adaptive and innate immune reactions and that these responses can be modified by ligands for other receptors expressed on the surface of mast cells. These various stimuli differe...

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

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

  17. Dysregulation of adaptive immune responses in complement C3-deficient patients

    Pekkarinen, Pirkka T.; Heikkila, Nelli; Kisand, Kai; Peterson, Paert; Botto, Marina; Daha, Mohamed R.; Drouet, Christian; Isaac, Lourdes; Helminen, Merja; Haahtela, Tari; Meri, Seppo; Jarva, Hanna; Arstila, T. Petteri

    2015-01-01

    In addition to its effector functions, complement is an important regulator of adaptive immune responses. Murine studies suggest that complement modulates helper T-cell differentiation, and Th1 responses in particular are impaired in the absence of functional complement. Here, we have studied humora

  18. Innate immunity is a key factor for the resolution of inflammation in asthma

    Cindy Barnig

    2015-03-01

    Full Text Available The resolution of inflammation is an integral and natural part of the physiological response to tissue injury, infection and allergens or other noxious stimuli. Resolution is now recognised as an active process with highly regulated cellular and biochemical events. Recent discoveries have highlighted that innate inflammatory cells have bimodal effector functions during the inflammatory response, including active roles during the resolution process. Several mediators displaying potent pro-resolving actions have recently been uncovered. Lipoxin A4, the lead member of this new class of pro-resolving mediators, has anti-inflammatory actions on type 2 innate lymphoid cells and pro-resolving actions through natural killer cells in asthma immunobiology. Eosinophils are also able to control crucial aspects of resolution through the generation of pro-resolving mediators. Uncontrolled asthma has been associated with a defect in the generation of specialised pro-resolving mediators, including lipoxin A4 and protectin D1. Thus, bioactive stable analogue mimetics of these mediators that can harness endogenous resolution mechanisms for inflammation may offer new therapeutic strategies for asthma and airway inflammation associated diseases.

  19. Interplay between inflammation, immune system and neuronal pathways: effect on gastrointestinal motility.

    De Winter, Benedicte-Y; De Man, Joris-G

    2010-11-28

    Sepsis is a systemic inflammatory response representing the leading cause of death in critically ill patients, mostly due to multiple organ failure. The gastrointestinal tract plays a pivotal role in the pathogenesis of sepsis-induced multiple organ failure through intestinal barrier dysfunction, bacterial translocation and ileus. In this review we address the role of the gastrointestinal tract, the mediators, cell types and transduction pathways involved, based on experimental data obtained from models of inflammation-induced ileus and (preliminary) clinical data. The complex interplay within the gastrointestinal wall between mast cells, residential macrophages and glial cells on the one hand, and neurons and smooth muscle cells on the other hand, involves intracellular signaling pathways, Toll-like receptors and a plethora of neuroactive substances such as nitric oxide, prostaglandins, cytokines, chemokines, growth factors, tryptases and hormones. Multidirectional signaling between the different components in the gastrointestinal wall, the spinal cord and central nervous system impacts inflammation and its consequences. We propose that novel therapeutic strategies should target inflammation on the one hand and gastrointestinal motility, gastrointestinal sensitivity and even pain signaling on the other hand, for instance by impeding afferent neuronal signaling, by activation of the vagal anti-inflammatory pathway or by the use of pharmacological agents such as ghrelin and ghrelin agonists or drugs interfering with the endocannabinoid system. PMID:21105185

  20. Immune modulation by ER stress and inflammation in the tumor microenvironment.

    Rodvold, Jeffrey J; Mahadevan, Navin R; Zanetti, Maurizio

    2016-09-28

    It is now increasingly evident that the immune system represents a barrier to tumor emergence, growth, and recurrence. Although this idea was originally proposed almost 50 years ago as the "immune surveillance hypothesis", it is commonly recognized that, with few rare exceptions, tumor cells always prevail. Thus, one of the central unsolved paradoxes of tumor immunology is how a tumor escapes immune control, which is reflected in the lack of effective autochthonous or vaccine-induced anti-tumor T cell responses. In this review, we discuss the role of the endoplasmic reticulum (ER) stress response/unfolded protein response (UPR) in the immunomodulation of myeloid cells and T cells. Specifically, we will discuss how the tumor cell UPR polarizes myeloid cells in a cell-extrinsic manner, and how in turn, thus polarized myeloid cells negatively affect T cell activation and clonal expansion. PMID:26525580

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

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

    2016-02-23

    Current studies have revealed the immune effects of graphene oxide (GO) and have utilized them as vaccine carriers and adjuvants. However, GO easily induces strong oxidative stress and inflammatory reaction at the site of injection. It is very necessary to develop an alternative adjuvant based on graphene oxide derivatives for improving immune responses and decreasing side effects. Carnosine (Car) is an outstanding and safe antioxidant. Herein, the feasibility and efficiency of ultrasmall graphene oxide decorated with carnosine as an alternative immune adjuvant were explored. OVA@GO-Car was prepared by simply mixing ovalbumin (OVA, a model antigen) with ultrasmall GO covalently modified with carnosine (GO-Car). We investigated the immunological properties of the GO-Car adjuvant in model mice. Results show that OVA@GO-Car can promote robust and durable OVA-specific antibody response, increase lymphocyte proliferation efficiency, and enhance CD4(+) T and CD8(+) T cell activation. The presence of Car in GO also probably contributes to enhancing the antigen-specific adaptive immune response through modulating the expression of some cytokines, including IL-6, CXCL1, CCL2, and CSF3. In addition, the safety of GO-Car as an adjuvant was evaluated comprehensively. No symptoms such as allergic response, inflammatory redness swelling, raised surface temperatures, physiological anomalies of blood, and remarkable weight changes were observed. Besides, after modification with carnosine, histological damages caused by GO-Car in lung, muscle, kidney, and spleen became weaken significantly. This study sufficiently suggest that GO-Car as a safe adjuvant can effectively enhance humoral and innate immune responses against antigens in vivo. PMID:26766427

  2. Soluble metals in residual oil fly ash alter innate and adaptive pulmonary immune responses to bacterial infection in rats

    The soluble metals of the pollutant, residual oil fly ash (ROFA), have been shown to alter pulmonary bacterial clearance in rats. The goal of this study was to determine the potential effects on both the innate and adaptive lung immune responses after bacterial infection in rats pre-exposed to the soluble metals in ROFA. Sprague-Dawley rats were intratracheally dosed (i.t.) at day 0 with ROFA (R-Total) (1.0 mg/100 g body weight), the soluble fraction of ROFA (R-Soluble), the soluble sample subject to a chelator (R-Chelex), or phosphate-buffered saline (Saline). On day 3, rats were administered an i.t. dose of 5 x 104 Listeria monocytogenes. On days 6, 8, and 10, bacterial pulmonary clearance was monitored and bronchoalveolar lavage (BAL) was performed on days 3 (pre-infection), 6, 8, and 10. A concentrated first fraction of lavage fluid was retained for analysis of lactate dehydrogenase and albumin to assess lung injury. BAL cell number, phenotype, and production of reactive oxygen (ROS) and nitrogen species (RNS) were assessed, and a variety of cytokines were measured in the BAL fluid. Rats pre-treated with R-Soluble showed elevated lung injury/cytotoxicity and increased cellular influx into the lungs. R-Soluble-treatment also altered ROS, RNS, and cytokine levels, and caused a degree of macrophage and T cell inhibition. These effects of R-Soluble result in increased pulmonary bacterial burden after infection. The results suggest that soluble metals in ROFA increase lung injury and inflammation, and alter both innate and adaptive pulmonary immune responses

  3. Inflammation Mediated Metastasis: Immune Induced Epithelial-To-Mesenchymal Transition in Inflammatory Breast Cancer Cells.

    Evan N Cohen

    Full Text Available Inflammatory breast cancer (IBC is the most insidious form of locally advanced breast cancer; about a third of patients have distant metastasis at initial staging. Emerging evidence suggests that host factors in the tumor microenvironment may interact with underlying IBC cells to make them aggressive. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT in these cells. We hypothesized that soluble factors secreted by activated immune cells can induce an EMT in IBC and thus promote metastasis. In a pilot study of 16 breast cancer patients, TNF-α production by peripheral blood T cells was correlated with the detection of circulating tumor cells expressing EMT markers. In a variety of IBC model cell lines, soluble factors from activated T cells induced expression of EMT-related genes, including FN1, VIM, TGM2, ZEB1. Interestingly, although IBC cells exhibited increased invasion and migration following exposure to immune factors, the expression of E-cadherin (CDH1, a cell adhesion molecule, increased uniquely in IBC cell lines but not in non-IBC cell lines. A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT. These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.

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

    Annunziato, Francesco; Romagnani, Chiara; Romagnani, Sergio

    2015-03-01

    The immune system has tailored its effector functions to optimally respond to distinct species of microbes. Based on emerging knowledge on the different effector T-cell and innate lymphoid cell (ILC) lineages, it is clear that the innate and adaptive immune systems converge into 3 major kinds of cell-mediated effector immunity, which we propose to categorize as type 1, type 2, and type 3. Type 1 immunity consists of T-bet(+) IFN-γ-producing group 1 ILCs (ILC1 and natural killer cells), CD8(+) cytotoxic T cells (TC1), and CD4(+) TH1 cells, which protect against intracellular microbes through activation of mononuclear phagocytes. Type 2 immunity consists of GATA-3(+) ILC2s, TC2 cells, and TH2 cells producing IL-4, IL-5, and IL-13, which induce mast cell, basophil, and eosinophil activation, as well as IgE antibody production, thus protecting against helminthes and venoms. Type 3 immunity is mediated by retinoic acid-related orphan receptor γt(+) ILC3s, TC17 cells, and TH17 cells producing IL-17, IL-22, or both, which activate mononuclear phagocytes but also recruit neutrophils and induce epithelial antimicrobial responses, thus protecting against extracellular bacteria and fungi. On the other hand, type 1 and 3 immunity mediate autoimmune diseases, whereas type 2 responses can cause allergic diseases. PMID:25528359

  5. [Severe inflammation during recovery from neutropenia: the immune reconstitution inflammatory syndrome following chemotherapy].

    van Lier, Dirk P T; Janssen, Nico A F; Snoeren, Miranda M; Verweij, Paul E; Blijlevens, Nicole M A; van der Velden, Walter J F M

    2015-01-01

    Immune reconstitution inflammatory syndrome (IRIS) occurs when a patient is recovering from a transient immunodeficiency and results in an uncontrolled inflammatory response to infectious agents and tissue damage. Symptoms such as fever and radiological signs seem to paradoxically appear or worsen, unmasking a previously unrecognized infection. The patient's clinical condition may then deteriorate as a result of increasing tissue damage and this may even lead to death. IRIS was initially described in patients suffering from a HIV infection who experienced immune recovery following the initiation of antiretroviral therapy. Increasingly, however, the syndrome is being reported in patients who are recovering from an episode of neutropenia following chemotherapy, hypomethylating agent use or a stem cell transplantation for the treatment of a solid tumour or haematological cancers. We describe two cases of IRIS following an episode of neutropenia in patients with a haematological malignancy and elaborate on the pathogenesis, diagnosis and treatment of IRIS in cancer patients. PMID:26246060

  6. A Systems Model for Immune Cell Interactions Unravels the Mechanism of Inflammation in Human Skin

    Valeyev, Najl V; Hundhausen, Christian; Umezawa, Yoshinori; Kotov, Nikolay V; Williams, Gareth; Clop, Alex; Ainali, Crysanthi; Ouzounis, Christos; Tsoka, Sophia; Nestle, Frank O

    2010-01-01

    Author Summary A functional immune system requires complex interactions among diverse cell types, mediated by a variety of cytokines. These interactions include phenomena such as positive and negative feedback loops that can be experimentally characterized by dose-dependent cytokine production measurements. However, any experimental approach is not only limited with regard to the number of cell-cell interactions that can be studied at a given time, but also does not have the capacity to asses...

  7. Neutrophil-Associated Central Nervous System Inflammation in Tuberculous Meningitis Immune Reconstitution Inflammatory Syndrome

    Marais, Suzaan; Wilkinson, Katalin A.; Lesosky, Maia; Coussens, Anna K.; Deffur, Armin; Pepper, Dominique J.; Schutz, Charlotte; Ismail, Zahiera; Meintjes, Graeme; Wilkinson, Robert J.

    2014-01-01

    Background. The immunopathogenesis of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) remains incompletely understood, and we know of only 1 disease site-specific study of the underlying immunology; we recently showed that Mycobacterium tuberculosis culture positivity and increased neutrophils in the cerebrospinal fluid (CSF) of patients with tuberculous meningitis (TBM) are associated with TBM-IRIS. In this study we investigated inflammatory mediators at the diseas...

  8. Central Nervous System and Innate Immune Mechanisms for Inflammation- and Cancer-induced Anorexia

    Ruud, Johan

    2012-01-01

    Anyone who has experienced influenza or a bacterial infection knows what it means to be ill. Apart from feeling feverish, experiencing aching joints and muscles, you lose the desire to eat. Anorexia, defined as loss of appetite or persistent satiety leading to reduced energy intake, is a hallmark of acute inflammatory disease. The anorexia is part of the acute phase response, triggered as the result of activation of the innate immune system with concomitant release of inflammatory mediators, ...

  9. Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior

    Wohleb, Eric S; McKim, Daniel B.; Sheridan, John F.; Godbout, Jonathan P.

    2015-01-01

    HIGHLIGHTS Psychological stress activates neuroendocrine pathways that alter immune responses. Stress-induced alterations in microglia phenotype and monocyte priming leads to aberrant peripheral and central inflammation. Elevated pro-inflammatory cytokine levels caused by microglia activation and recruitment of monocytes to the brain contribute to development and persistent anxiety-like behavior. Mechanisms that mediate interactions between microglia, endothelial cells, and macro...

  10. Persisting Inflammation and Chronic Immune Activation but Intact Cognitive Function in HIV-Infected Patients After Long-Term Treatment With Combination Antiretroviral Therapy

    Pedersen, Karin K; Pedersen, Maria; Gaardbo, Julie C;

    2013-01-01

    Impaired cognitive function in HIV-infected patients has been suggested. Treatment with combination antiretroviral therapy (cART) restores CD4⁺ cell counts and suppresses viral replication, but immune activation and inflammation may persist. The aim of the study was to examine if cognitive functi...

  11. Biogenesis pathways of RNA guides in archaeal and bacterial CRISPR-Cas adaptive immunity

    Charpentier, Emmanuelle; Richter, Hagen; van der Oost, John; White, Malcolm F

    2015-01-01

    CRISPR-Cas is an RNA-mediated adaptive immune system that defends bacteria and archaea against mobile genetic elements. Short mature CRISPR RNAs (crRNAs) are key elements in the interference step of the immune pathway. A CRISPR array composed of a series of repeats interspaced by spacer sequences acquired from invading mobile genomes is transcribed as a precursor crRNA (pre-crRNA) molecule. This pre-crRNA undergoes one or two maturation steps to generate the mature crRNAs that guide CRISPR-as...

  12. Hapten may play an important role in food allergen-related intestinal immune inflammation

    Zhi-Qiang Liu

    2011-01-01

    Full Text Available There has been a significant increase in the prevalence of allergic diseases especially over the past 2 to 3 decades. However, the etiology and pathogenesis of food allergy are not fully understood. In recent years, with the huge increase in atopic disease, there has also been an increase in dietary hapten exposure. Allergic reactions to chemical haptens occur, in the overwhelming majority of cases, as an inflammatory reaction in the skin to direct contact with haptens. While reactions to haptens on other epithelial surfaces have only rarely been investigated; it is still not clear whether haptens can combine the food antigens and play a role in the induction of food allergen-related inflammation in the intestine. Further research is needed to reveal the underlying mechanism.

  13. The effect of the CCR5-delta32 deletion on global gene expression considering immune response and inflammation

    Hütter Gero

    2011-10-01

    Full Text Available Abstract Background The natural function of the C-C chemokine receptor type 5 (CCR5 is poorly understood. A 32 base pair deletion in the CCR5 gene (CCR5-delta32 located on chromosome 3 results in a non-functional protein. It is supposed that this deletion causes an alteration in T-cell response to inflammation. For example, the presence of the CCR5-delta32 allele in recipients of allografts constitutes as an independent and protective factor associated with a decreased risk of graft-versus-host disease (GVHD and graft rejection. However, the mechanism of this beneficial effect of the deletion regarding GVHD is unknown. In this survey we searched for a CCR5-delta32 associated regulation of critical genes involved in the immune response and the development of GVHD. Methods We examined CD34+ hematopoietic progenitor cells derived from bone marrow samples from 19 healthy volunteers for the CCR5-delta32 deletion with a genomic PCR using primers flanking the site of the deletion. Results 12 individuals were found to be homozygous for CCR5 WT and 7 carried the CCR5-delta32 deletion heterozygously. Global gene expression analysis led to the identification of 11 differentially regulated genes. Six of them are connected with mechanisms of immune response and control: LRG1, CXCR2, CCRL2, CD6, CD7, WD repeat domain, and CD30L. Conclusions Our data indicate that the CCR5-delta32 mutation may be associated with differential gene expression. Some of these genes are critical for immune response, in the case of CD30L probably protective in terms of GVHD.

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

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

    2016-01-01

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

  15. Inhibitor of apoptosis (IAP) proteins in regulation of inflammation and innate immunity

    Damgaard, Rune B; Gyrd-Hansen, Mads

    2011-01-01

    as important regulators of innate immune signaling downstream of pattern recognition receptors (PRRs) such as Toll-like receptor 4 (TLR4), the nucleotide-binding oligomerization domain 1 (NOD1) and NOD2 receptors, and the retinoic acid-inducible gene (RIG)-I receptor. Recent evidence suggests that c......IAP1, cIAP2, and XIAP facilitate ubiquitin-dependent signaling activated by these PRRs and mediate activation of nuclear factor-kappa B (NF-kappaB) transcription factors as well as the MAP kinases p38 and JNK. Here, we review the current understanding of IAP-mediated PRR signaling and how IAP proteins...

  16. Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation.

    Cao, Zhifang; Conway, Kara L; Heath, Robert J; Rush, Jason S; Leshchiner, Elizaveta S; Ramirez-Ortiz, Zaida G; Nedelsky, Natalia B; Huang, Hailiang; Ng, Aylwin; Gardet, Agnès; Cheng, Shih-Chin; Shamji, Alykhan F; Rioux, John D; Wijmenga, Cisca; Netea, Mihai G; Means, Terry K; Daly, Mark J; Xavier, Ramnik J

    2015-10-20

    CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigating CARD9 regulation. We showed that the protective variant of CARD9, which is C-terminally truncated, acted in a dominant-negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that similar to Card9-deficient mice, Trim62-deficient mice had increased susceptibility to fungal infection. In this study, we utilized a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation. PMID:26488816

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

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

    2015-10-01

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

  18. The association between obesity, cardiometabolic disease biomarkers, and innate immunity-related inflammation in Canadian adults

    Da Costa LA

    2012-10-01

    Full Text Available Laura A Da Costa,1,2,*Paul Arora,2,3,* Bibiana García-Bailo,1,2 Mohamed Karmali,1,2 Ahmed El-Sohemy,1 Alaa Badawi2 1Department of Nutritional Sciences, University of Toronto; 2Office of Biotechnology and Population Health, Public Health Agency of Canada; 3Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada *These authors contributed equally to this article Introduction: Obesity is associated with a state of chronic inflammation, and increased cardiometabolic disease risk. The present study examined the relationship between body mass index (BMI and cardiometabolic and inflammatory biomarkers among normal weight, overweight, and obese Canadian adults.Methods: Subjects (n = 1805, aged 18 to 79 years from the Canadian Health Measures Survey (CHMS were examined for associations between BMI, cardiometabolic markers (apolipoprotein [Apo] A1, ApoB, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol, total cholesterol/HDL ratio [total:HDL-C ratio], triglycerides, and glycosylated hemoglobin [HbA1c], inflammatory factors (C-reactive protein [CRP], fibrinogen, and homocysteine, and 25-hydroxyvitamin D [25(OHD]. Bootstrap weights for variance and sampling weights for point estimates were applied to account for the complex survey design. Linear regression models adjusted for age, sex, physical activity, smoking status, and ethnicity (in addition to season of clinic visit, for vitamin D analyses only were used to examine the association between cardiometabolic markers, inflammatory factors, and BMI in Canadian adults.Results: All biomarkers were significantly associated with BMI (P ≤ 0.001. ApoA1 (β = −0.31, P < 0.0001, HDL-C (β = −0.61, P < 0.0001, and 25(OHD (β = −0.25, P < 0.0001 were inversely associated with BMI, while all other biomarkers showed positive linear associations. Distinct patterns of association were noted among normal weight, overweight

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

    Kieslich, Chris A.; Dimitrios Morikis

    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 compl...

  20. Shades of grey-the blurring view of innate and adaptive immunity

    Lanier, LL

    2013-01-01

    This special issue of Nature Reviews Immunology focuses on the types of lymphocyte that blur the traditional boundaries between the innate and adaptive immune systems. The development and functional properties of 'innate-like' B and T cells and natural killer (NK) cells are reviewed and the emerging understanding of newly discovered innate lymphoid cells (ILCs) is considered. © 2013 Macmillan Publishers Limited. All rights reserved.

  1. Can We Translate Vitamin D Immunomodulating Effect on Innate and Adaptive Immunity to Vaccine Response?

    Pierre Olivier Lang

    2015-03-01

    Full Text Available Vitamin D (VitD, which is well known for its classic role in the maintenance of bone mineral density, has now become increasingly studied for its extra-skeletal roles. It has an important influence on the body’s immune system and modulates both innate and adaptive immunity and regulates the inflammatory cascade. In this review our aim was to describe how VitD might influence immune responsiveness and its potential modulating role in vaccine immunogenicity. In the first instance, we consider the literature that may provide molecular and genetic support to the idea that VitD status may be related to innate and/or adaptive immune response with a particular focus on vaccine immunogenicity and then discuss observational studies and controlled trials of VitD supplementation conducted in humans. Finally, we conclude with some knowledge gaps surrounding VitD and vaccine response, and that it is still premature to recommend “booster” of VitD at vaccination time to enhance vaccine response.

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

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

    2015-01-01

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

  3. The Immune System and the Role of Inflammation in Perinatal Depression.

    Leff-Gelman, Philippe; Mancilla-Herrera, Ismael; Flores-Ramos, Mónica; Cruz-Fuentes, Carlos; Reyes-Grajeda, Juan Pablo; García-Cuétara, María Del Pilar; Bugnot-Pérez, Marielle Danitza; Pulido-Ascencio, David Ellioth

    2016-08-01

    Major depression during pregnancy is a common psychiatric disorder that arises from a complex and multifactorial etiology. Psychosocial stress, sex, hormones, and genetic vulnerability increase the risk for triggering mood disorders. Microglia and toll-like receptor 4 play a crucial role in triggering wide and varied stress-induced responses mediated through activation of the inflammasome; this leads to the secretion of inflammatory cytokines, increased serotonin metabolism, and reduction of neurotransmitter availability along with hypothalamic-pituitary-adrenal axis hyperactivity. Dysregulation of this intricate neuroimmune communication network during pregnancy modifies the maternal milieu, enhancing the emergence of depressive symptoms and negative obstetric and neuropsychiatric outcomes. Although several studies have clearly demonstrated the role of the innate immune system in major depression, it is still unclear how the placenta, the brain, and the monoaminergic and neuroendocrine systems interact during perinatal depression. Thus, in the present review we describe the cellular and molecular interactions between these systems in major depression during pregnancy, proposing that the same stress-related mechanisms involved in the activation of the NLRP3 inflammasome in microglia and peripheral myeloid cells in depressed patients operate in a similar fashion in the neuroimmune placenta during perinatal depression. Thus, activation of Toll-like receptor 2 and 4 signaling and the NLRP3 inflammasome in placental immune cells may promote a shift of the Th1/Th2 bias towards a predominant Th1/Th17 inflammatory response, associated with increased secretion of pro-inflammatory cytokines, among other secreted autocrine and paracrine mediators, which play a crucial role in triggering and/or exacerbating depressive symptoms during pregnancy. PMID:27432060

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

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

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

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

    2013-04-01

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

  6. Tamoxifen persistently disrupts the humoral adaptive immune response of gilthead seabream (Sparus aurata L.).

    Rodenas, M C; Cabas, I; Abellán, E; Meseguer, J; Mulero, V; García-Ayala, A

    2015-12-01

    There is increasing concern about the possible effect of pharmaceutical compounds may have on the fish immune system. Bath exposition of 17α-ethynylestradiol (EE2), a synthetic estrogen used in oral contraceptives, altered the immune response of the gilthead seabream (Sparus aurata L.), a marine hermaphrodite teleost. Tamoxifen (Tmx) is a selective estrogen-receptor modulator used in hormone replacement therapy, the effects of which are unknown in fish immunity. This study aims to investigate the effects of dietary administration of EE2 (5 μg/g food) and Tmx (100 μg/g food) on the immune response of gilthead seabream, and the capacity of the immune system to recover its functionality after a recovery period. The results show for the first time the reversibility of the effect of EE2 and Tmx on the fish immune response. Tmx promoted a transient alteration in hepatic vitellogenin gene expression of a different magnitude to that produced by EE2. Both, EE2 and Tmx inhibited the induction of interleukin-1β gene expression while reversed the inhibition of ROI production in leukocytes following vaccination. However, none of these effects were observed after ceasing EE2 and Tmx exposure. EE2 and Tmx stimulated the antibody response of vaccinated fish although Tmx, but not EE2, altered the antibody response and modulated the percentage of IgM(+) B lymphocytes of vaccinated fish during the recovery phase. Taken together, our results suggest that EE2 and Tmx might alter the capacity of fish to appropriately respond to infection and show that Tmx has a long-lasting effect on humoral adaptive immunity. PMID:26234710

  7. The acute effect of ingesting a quercetin-based supplement on exercise-induced inflammation and immune changes in runners.

    Konrad, Manuela; Nieman, David C; Henson, Dru A; Kennerly, Krista M; Jin, Fuxia; Wallner-Liebmann, Sandra J

    2011-08-01

    This study tested the acute anti-inflammatory and immune-modulating influence of a quercetin-based supplement consumed by endurance athletes 15 min before an intense 2-hr run. In this randomized, crossover study, 20 runners (11 men, 9 women, age 38.4 ± 2.1 yr) completed two 2-hr treadmill runs at 70% VO(2max) (3 wk apart). Subjects ingested either 4 quercetin-based chews (Q-chew) or placebo chews (PL) 15 min before the runs. The 4 Q-chews provided 1,000 mg quercetin, 120 mg epigallocatechin 3-gallate, 400 mg isoquercetin, 400 mg each eicosapentaenoic acid and docosahexaenoic acid, 1,000 mg vitamin C, and 40 mg niacinamide. Subjects provided blood samples 30 min before, immediately after, and 1 hr postexercise and were analyzed for plasma quercetin, total blood leukocytes (WBC), C-reactive protein (CRP), 9 cytokines (IL-6, TNFα, GM-CSF, IFNγ, IL-1β, IL-2, IL-8, IL-10, and IL-12p70), granulocyte (GR) and monocyte (MO) phagocytosis (PHAG), and oxidative-burst activity (OBA). Plasma quercetin increased from 80.0 ± 26.0 μg/L to 6,337 ± 414 μg/L immediately postexercise and 4,324 ± 310 μg/L 1 hr postexercise after ingestion of Q-chews, compared with no change in PL (p < .001). Exercise caused significant increases in, CRP, GM-CSF, IL-10, IL-1β, IL-2, IL-6, IL-8, TNFα, GR-PHAG, and MO-PHAG and decreases in GR-OBA and MO-OBA, but no differences in the pattern of change were measured between Q-chew and PL trials. Acute ingestion of Q-chews 15 min before heavy exertion caused a strong increase in plasma quercetin levels but did not counter postexercise inflammation or immune changes relative to placebo. PMID:21813917

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

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

    2014-01-01

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

  9. Clinical Application of Development of Nonantibiotic Macrolides That Correct Inflammation-Driven Immune Dysfunction in Inflammatory Skin Diseases

    Carmen Rodriguez-Cerdeira

    2012-01-01

    Full Text Available Background. Inflammation-driven immune dysfunction supports the development of several chronic human disorders including skin diseases. Nonantibiotic macrolides have anti-inflammatory and/or immunomodulatory activity that suggests the exploitation of these in the treatment of skin diseases characterized by inflammatory disorders. Materials and Methods. We performed an extensive review of the nonantibiotic macrolide literature published between 2005 and 2012, including cross-references of any retrieved articles. We also included some data from our own experience. Results. Calcineurin antagonists such as tacrolimus and ascomycins (e.g., pimecrolimus act by inhibiting the activation of the nuclear factor for activated T cells (NFAT. There are new applications for these macrolides that have been available for several years and have been applied to skin and hair disorders such as atopic dermatitis, oral lichen planus, vitiligo, chronic autoimmune urticaria, rosacea, alopecia areata, pyoderma gangrenosum, Behcet’s disease, neutrophilic dermatosis, and lupus erythematosus. We also reviewed new macrolides, like rapamycin, everolimus, and temsirolimus. In addition to the literature review, we report a novel class of nonantibiotic 14-member macrocycle with anti-inflammatory and immunomodulatory effects. Conclusions. This paper summarizes the most important clinical studies and case reports dealing with the potential benefits of nonantibiotic macrolides which have opened new avenues in the development of anti-inflammatory strategies in the treatment of cutaneous disorders.

  10. Understanding inflammation in juvenile idiopathic arthritis: How immune biomarkers guide clinical strategies in the systemic onset subtype.

    Swart, Joost F; de Roock, Sytze; Prakken, Berent J

    2016-09-01

    The translation of basic insight in immunological mechanisms underlying inflammation into clinical practice of inflammatory diseases is still challenging. Here we describe how-through continuous dialogue between bench and bedside-immunological knowledge translates into tangible clinical use in a complex inflammatory disease, juvenile idiopathic arthritis (JIA). Systemic JIA (sJIA) is an autoinflammatory disease, leading to the very successful use of IL-1 antagonists. Further immunological studies identified new immune markers for diagnosis, prediction of complications, response to and successful withdrawal of therapy. Myeloid related protein (MRP)8, MRP14, S100A12, and Interleukin-18 are already used daily in clinic as markers for active sJIA. For non-sJIA subtypes, HLA-B27, antinuclear-antibodies, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein are still used for classification, prognosis or active disease. MRP8, MRP14, and S100A12 are now under study for clinical practice. We believe that with biomarkers, algorithms can soon be designed for the individual risk of disease, complications, damage, prediction of response to, and successful withdrawal of therapy. In that way, less time will be lost and less pain will be suffered by the patients. In this review, we describe the current status of immunological biomarkers used in diagnosis and treatment of JIA. PMID:27461267

  11. A Comparison of the Adaptive Immune Response between Recovered Anthrax Patients and Individuals Receiving Three Different Anthrax Vaccines

    Thomas R. Laws; Tinatin Kuchuloria; Nazibriola Chitadze; Little, Stephen F.; Webster, Wendy M.; Debes, Amanda K; Salome Saginadze; Nikoloz Tsertsvadze; Mariam Chubinidze; Robert G Rivard; Shota Tsanava; Dyson, Edward H.; Andrew J H Simpson; Hepburn, Matthew J; Nino Trapaidze

    2016-01-01

    Several different human vaccines are available to protect against anthrax. We compared the human adaptive immune responses generated by three different anthrax vaccines or by previous exposure to cutaneous anthrax. Adaptive immunity was measured by ELISPOT to count cells that produce interferon (IFN)-γ in response to restimulation ex vivo with the anthrax toxin components PA, LF and EF and by measuring circulating IgG specific to these antigens. Neutralising activity of antisera against anthr...

  12. THE INFLUENCE OF HUMORAL IMMUNITY ANTIENDOTOXIN RESPONSE TO INDICATORS OF SYSTEMIC INFLAMMATION IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

    D. V. Shaduro

    2016-01-01

    dysfunction in the antiendotoxin immune response (AEIR in SLE patients, namely increasing concentrations of specific anti-LPS-Ig. Identified growth of indicators of systemic inflammation correlated with indicators of AEIR, that confirms their mutual influence, which contributes to the lesion of organ-targets and can aggravate the manifestation and course of SLE. Normalization of AEIR, elimination of LPS may be a new way of treatment for SLE patients

  13. Optimal reactive power flow incorporating static voltage stability based on multi-objective adaptive immune algorithm

    People have paid more attention to enhancing voltage stability margin since voltage collapses happened in some power systems recently. This paper proposes an optimal reactive power flow (ORPF) incorporating static voltage stability based on a multi-objective adaptive immune algorithm (MOAIA). The main idea of the proposed algorithm is to add two parts to an existing immune algorithm. The first part defines both partial affinity and global affinity to evaluate the antibody affinity to the multi-objective functions. The second part uses adaptive crossover, mutation and clone rates for antibodies to maintain the antibodies diversity. Hence, the proposed algorithm can achieve a dynamic balance between individual diversity and population convergence. The paper describes ORPF's multi-objective functional mathematical model and the constraint conditions. The problems associated with the antibody are also discussed in detail. The proposed method has been tested in the IEEE-30 system and compared with IGA (immune genetic algorithm). The results show that the proposed algorithm has improved performance over the IGA

  14. Parainflammation, chronic inflammation and age-related macular degeneration

    Chen, Mei; Xu, Heping

    2015-01-01

    Inflammation is an adaptive response of the immune system to noxious insults to maintain homeostasis and restore functionality. The retina is considered an immune privileged tissue due to its unique anatomical and physiological properties. During aging, the retina suffers from a low-grade chronic oxidative insult, which sustains for decades and increases in level with advancing age. As a result, the retinal innate immune system, particularly microglia and the complement system, undergo low le...

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

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

    2013-12-01

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

  16. Biological limits to reduction in rates of coronary heart disease: a punctuated equilibrium approach to immune cognition, chronic inflammation, and pathogenic social hierarchy

    Wallace, Rodrick; Wallace, Deborah; Robert G Wallace

    2002-01-01

    On both empirical and theoretical grounds we find that a particular form of social hierarchy, here characterized as 'pathogenic', can, from the earliest phases of life, exert a formal analog to evolutionary selection pressure, literally writing a permanent image of itself upon immune function as chronic vascular inflammation and its consequences. The staged nature of resulting disease emerges 'naturally' as an analog to punctuated equilibrium in evolutionary theory. Exposure differs accordi...

  17. Medroxyprogesterone Acetate Modulates Remodeling, Immune Cell Census, and Nerve Fibers in the Cervix of a Mouse Model for Inflammation-induced Preterm Birth

    Yellon, Steven M.; Ebner, Charlotte A.; Elovitz, Michal A.

    2008-01-01

    To determine whether a progestational agent can modify inflammation-induced preterm cervical ripening, mice on day 15 of gestation were given an intrauterine injection of (1) saline, (2) lipopolysaccharide, (3) an intramuscular injection of medroxyprogesterone acetate alone prior to lipopolysaccharide, or (4) medroxyprogesterone acetate alone. Cervices were obtained 6 hours later, then fixed, sectioned, and processed to stain collagen structure or to identify immune cells or nerve fibers. Cer...

  18. The diversity-generating benefits of a prokaryotic adaptive immune system.

    van Houte, Stineke; Ekroth, Alice K E; Broniewski, Jenny M; Chabas, Hélène; Ashby, Ben; Bondy-Denomy, Joseph; Gandon, Sylvain; Boots, Mike; Paterson, Steve; Buckling, Angus; Westra, Edze R

    2016-04-21

    Prokaryotic CRISPR-Cas adaptive immune systems insert spacers derived from viruses and other parasitic DNA elements into CRISPR loci to provide sequence-specific immunity. This frequently results in high within-population spacer diversity, but it is unclear if and why this is important. Here we show that, as a result of this spacer diversity, viruses can no longer evolve to overcome CRISPR-Cas by point mutation, which results in rapid virus extinction. This effect arises from synergy between spacer diversity and the high specificity of infection, which greatly increases overall population resistance. We propose that the resulting short-lived nature of CRISPR-dependent bacteria-virus coevolution has provided strong selection for the evolution of sophisticated virus-encoded anti-CRISPR mechanisms. PMID:27074511

  19. Observation of curative effect in antibiotics associated diarrhea children treated by pidotimod and the influence on the inflammation factors and the immune function

    Zhao-Yang Yin; Yao Chen; Ting Zhao

    2016-01-01

    Objective:To explore the curative effect in antibiotics associated diarrhea children treated by pidotimod and the influence on the inflammation factors and the immune function.Methods:A total of 82 cases antibiotic associated diarrhea children were divided into control group and observation group according to random number table method,41 cases in each group, children in two groups were given conventional treatment, on this basis, children in observation group were with pidotimod treatment, they were treated for 2 weeks, compared the clinical efficacy and immune globulin: IgA, IgG, IgM, T cell subgroup: CD3+, CD4+, CD8+, CD4+/CD8+, and inflammation factors: tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). Results:The total effective rate in control group was 75.61%,it was significantly lower than 95.12% in observation group; The levels of CD3+,CD4+,CD4+/CD8+, IgA, IgG after treatment in two groups were significantly rised while the levels of TNF-α, IL-6 were significantly reduced than before treatment, The amplitude of index above in observation group was greater than the control group, the difference were all statistically significant.Conclusion: The curative effect in antibiotics associated diarrhea children treated by pidotimodi is obvious, it can reduce inflammation, improve immunity.

  20. Innate and adaptive immune interactions at the fetal-maternal interface in healthy human pregnancy and pre-eclampsia.

    Hsu, Peter; Nanan, Ralph Kay Heinrich

    2014-01-01

    Maternal immune tolerance of the fetus is indispensable for a healthy pregnancy outcome. Nowhere is this immune tolerance more important than at the fetal-maternal interface - the decidua, the site of implantation, and placentation. Indeed, many lines of evidence suggest an immunological origin to the common pregnancy-related disorder, pre-eclampsia. Within the innate immune system, decidual NK cells and antigen presenting cells (including dendritic cells and macrophages) make up a large proportion of the decidual leukocyte population, and are thought to modulate vascular remodeling and trophoblast invasion. On the other hand, within the adaptive immune system, Foxp3(+) regulatory T cells are crucial for ensuring immune tolerance toward the semi-allogeneic fetus. Additionally, another population of CD4(+)HLA-G(+) suppressor T cells has also been identified as a potential player in the maintenance of immune tolerance. More recently, studies are beginning to unravel the potential interactions between the innate and the adaptive immune system within the decidua, that are required to maintain a healthy pregnancy. In this review, we discuss the recent advances exploring the complex crosstalk between the innate and the adaptive immune system during human pregnancy. PMID:24734032

  1. Filoviruses and the balance of innate, adaptive, and inflammatory responses.

    Mohamadzadeh, Mansour; Chen, Lieping; Olinger, Gene G; Pratt, William D; Schmaljohn, Alan L

    2006-01-01

    The Filoviruses Marburg virus and Ebola virus are among the deadliest of human pathogens, causing fulminant hemorrhagic fevers typified by overmatched specific immune responses and profuse inflammatory responses. Keys to both vaccination and treatment may reside, first, in the understanding of immune dysfunctions that parallel Filoviral disease and, second, in devising ways to redirect and restore normal immune function as well as to mitigate inflammation. Here, we describe how Filoviral infections may subvert innate immune responses through perturbances of dendritic cells and neutrophils, with particular emphasis on the downstream effects on adaptive immunity and inflammation. We suggest that pivotal events may be subject to therapeutic intervention as Filoviruses encounter immune processes. PMID:17201655

  2. Coinfection with human herpesvirus 8 is associated with persistent inflammation and immune activation in virologically suppressed HIV-infected patients.

    Mar Masiá

    -media thickness were not different according to HHV-8 serostatus.In virologically suppressed HIV-infected patients, coinfection with HHV-8 is associated with increased inflammation and immune activation. This might contribute to increase the risk of non-AIDS events, including accelerated atherosclerotic disease.

  3. Hypercholesterolemia Tunes Hematopoietic Stem/Progenitor Cells for Inflammation and Atherosclerosis

    Xiaojuan Ma; Yingmei Feng

    2016-01-01

    As the pathological basis of cardiovascular disease (CVD), atherosclerosis is featured as a chronic inflammation. Hypercholesterolemia is an independent risk factor for CVD. Accumulated studies have shown that hypercholesterolemia is associated with myeloid cell expansion, which stimulates innate and adaptive immune responses, strengthens inflammation, and accelerates atherosclerosis progression. Hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM) expresses a panel of lipoprotein r...

  4. Toxoplasma gondii oral infection induces intestinal inflammation and retinochoroiditis in mice genetically selected for immune oral tolerance resistance.

    Raul Ramos Furtado Dias

    Full Text Available Toxoplasmosis is a worldwide disease with most of the infections originating through the oral route and generates various pathological manifestations, ranging from meningoencephalitis to retinochoroiditis and inflammatory bowel disease. Animal models for these pathologies are scarce and have limitations. We evaluated the outcome of Toxoplasma gondii oral infection with 50 or 100 cysts of the ME-49 strain in two lines of mice with extreme phenotypes of susceptibility (TS or resistance (TR to immune oral tolerance. Therefore, the aim of this study was to evaluate the behaviour of TS and TR mice, orally infected by T. gondii, and determine its value as a model for inflammatory diseases study. Mortality during the acute stage of the infection for TR was 50% for both dosages, while 10 and 40% of the TS died after infection with these respective dosages. In the chronic stage, the remaining TS succumbed while TR survived for 90 days. The TS displayed higher parasite load with lower intestinal inflammation and cellular proliferation, notwithstanding myocarditis, pneumonitis and meningoencephalitis. TR presented massive necrosis of villi and crypt, comparable to inflammatory bowel disease, with infiltration of lymphoid cells in the lamina propria of the intestines. Also, TR mice infected with 100 cysts presented intense cellular infiltrate within the photoreceptor layer of the eyes, changes in disposition and morphology of the retina cell layers and retinochoroiditis. During the infection, high levels of IL-6 were detected in the serum of TS mice and TR mice presented high amounts of IFN-γ and TNF-α. Both mice lineages developed different disease outcomes, but it is emphasized that TR and TS mice presented acute and chronic stages of the infection, demonstrating that the two lineages offer an attractive model for studying toxoplasmosis.

  5. The Carbomer-Lecithin Adjuvant Adjuplex Has Potent Immunoactivating Properties and Elicits Protective Adaptive Immunity against Influenza Virus Challenge in Mice

    Wegmann, Frank; Moghaddam, Amin E.; Schiffner, Torben; Gartlan, Kate H.; Powell, Timothy J.; Russell, Rebecca A.; Baart, Matthijs; Carrow, Emily W.

    2015-01-01

    The continued discovery and development of adjuvants for vaccine formulation are important to safely increase potency and/or reduce the antigen doses of existing vaccines and tailor the adaptive immune response to newly developed vaccines. Adjuplex is a novel adjuvant platform based on a purified lecithin and carbomer homopolymer. Here, we analyzed the adjuvant activity of Adjuplex in mice for the soluble hemagglutinin (HA) glycoprotein of influenza A virus. The titration of Adjuplex revealed an optimal dose of 1% for immunogenicity, eliciting high titers of HA-specific IgG but inducing no significant weight loss. At this dose, Adjuplex completely protected mice from an otherwise lethal influenza virus challenge and was at least as effective as the adjuvants monophosphoryl lipid A (MPL) and alum in preventing disease. Adjuplex elicited balanced Th1-/Th2-type immune responses with accompanying cytokines and triggered antigen-specific CD8+ T-cell proliferation. The use of the peritoneal inflammation model revealed that Adjuplex recruited dendritic cells (DCs), monocytes, and neutrophils in the context of innate cytokine and chemokine secretion. Adjuplex neither triggered classical maturation of DCs nor activated a pathogen recognition receptor (PRR)-expressing NF-κB reporter cell line, suggesting a mechanism of action different from that reported for classical pathogen-associated molecular pattern (PAMP)-activated innate immunity. Taken together, these data reveal Adjuplex to be a potent and well-tolerated adjuvant with application for subunit vaccines. PMID:26135973

  6. Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy – ACTG A5286

    Tenorio, Allan R.; Chan, Ellen S; Bosch, Ronald J.; Macatangay, Bernard J.C.; Read, Sarah W.; Yesmin, Suria; Taiwo, Babafemi; Margolis, David M.; Jacobson, Jeffrey M.; Landay, Alan L.; Wilson, Cara C.; Mellors, John W.; Keshavarzian, Ali; Rodriguez, Benigno; Aziz, Mariam

    2014-01-01

    Background. Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART).

  7. Host Resistance and Immune Aging.

    Bandaranayake, Thilinie; Shaw, Albert C

    2016-08-01

    Human immune system aging results in impaired responses to pathogens or vaccines. In the innate immune system, which mediates the earliest pro-inflammatory responses to immunologic challenge, processes ranging from Toll-like Receptor function to Neutrophil Extracellular Trap formation are generally diminished in older adults. Dysregulated, enhanced basal inflammation with age reflecting activation by endogenous damage-associated ligands contributes to impaired innate immune responses. In the adaptive immune system, T and B cell subsets and function alter with age. The control of cytomegalovirus infection, particularly in the T lineage, plays a dominant role in the differentiation and diversity of the T cell compartment. PMID:27394014

  8. Within-host co-evolution of chronic viruses and the adaptive immune system

    Nourmohammad, Armita

    We normally think of evolution occurring in a population of organisms, in response to their external environment. Rapid evolution of cellular populations also occurs within our bodies, as the adaptive immune system works to eliminate infection. Some pathogens, such as HIV, are able to persist in a host for extended periods of time, during which they also evolve to evade the immune response. In this talk I will introduce an analytical framework for the rapid co-evolution of B-cell and viral populations, based on the molecular interactions between them. Since the co-evolution of antibodies and viruses is perpetually out of equilibrium, I will show how to quantify the amount of adaptation in each of the two populations by analysis of their co-evolutionary history. I will discuss the consequences of competition between lineages of antibodies, and characterize the fate of a given lineage dependent on the state of the antibody and viral populations. In particular, I will discuss the conditions for emergence of highly potent broadly neutralizing antibodies, which are now recognized as critical for designing an effective vaccine against HIV.

  9. Preserved antiviral adaptive immunity following polyclonal antibody immunotherapy for severe murine influenza infection

    Stevens, Natalie E.; Hatjopolous, Antoinette; Fraser, Cara K.; Alsharifi, Mohammed; Diener, Kerrilyn R.; Hayball, John D.

    2016-01-01

    Passive immunotherapy may have particular benefits for the treatment of severe influenza infection in at-risk populations, however little is known of the impact of passive immunotherapy on the formation of memory responses to the virus. Ideally, passive immunotherapy should attenuate the severity of infection while still allowing the formation of adaptive responses to confer protection from future exposure. In this study, we sought to determine if administration of influenza-specific ovine polyclonal antibodies could inhibit adaptive immune responses in a murine model of lethal influenza infection. Ovine polyclonal antibodies generated against recombinant PR8 (H1N1) hemagglutinin exhibited potent prophylactic capacity and reduced lethality in an established influenza infection, particularly when administered intranasally. Surviving mice were also protected against reinfection and generated normal antibody and cytotoxic T lymphocyte responses to the virus. The longevity of ovine polyclonal antibodies was explored with a half-life of over two weeks following a single antibody administration. These findings support the development of an ovine passive polyclonal antibody therapy for treatment of severe influenza infection which does not affect the formation of subsequent acquired immunity to the virus. PMID:27380890

  10. Preserved antiviral adaptive immunity following polyclonal antibody immunotherapy for severe murine influenza infection.

    Stevens, Natalie E; Hatjopolous, Antoinette; Fraser, Cara K; Alsharifi, Mohammed; Diener, Kerrilyn R; Hayball, John D

    2016-01-01

    Passive immunotherapy may have particular benefits for the treatment of severe influenza infection in at-risk populations, however little is known of the impact of passive immunotherapy on the formation of memory responses to the virus. Ideally, passive immunotherapy should attenuate the severity of infection while still allowing the formation of adaptive responses to confer protection from future exposure. In this study, we sought to determine if administration of influenza-specific ovine polyclonal antibodies could inhibit adaptive immune responses in a murine model of lethal influenza infection. Ovine polyclonal antibodies generated against recombinant PR8 (H1N1) hemagglutinin exhibited potent prophylactic capacity and reduced lethality in an established influenza infection, particularly when administered intranasally. Surviving mice were also protected against reinfection and generated normal antibody and cytotoxic T lymphocyte responses to the virus. The longevity of ovine polyclonal antibodies was explored with a half-life of over two weeks following a single antibody administration. These findings support the development of an ovine passive polyclonal antibody therapy for treatment of severe influenza infection which does not affect the formation of subsequent acquired immunity to the virus. PMID:27380890

  11. The antimicrobial/elastase inhibitor elafin regulates lung dendritic cells and adaptive immunity.

    Roghanian, Ali; Williams, Steven E; Sheldrake, Tara A; Brown, Tom I; Oberheim, Karen; Xing, Zhou; Howie, Sarah E M; Sallenave, Jean-Michel

    2006-05-01

    Infections with bacteria and viruses such as adenovirus are a feature of chronic lung diseases such as chronic obstructive pulmonary diseases (COPD), and may be instrumental in the generation of disease exacerbations. We have previously shown in acute models that elafin (a lung natural chemotactic molecule for macrophages and neutrophils, with potent antimicrobial and neutrophil elastase inhibitor activity) is upregulated in infection and modulates innate immunity. Here we present data using two independent systems of elafin overexpression in vivo (recombinant adenovirus [Ad-elafin] and an elafin transgenic mouse line) to examine the function of elafin in adaptive immunity. We show that elafin increases the number (immunofluorescence) and activation status (flow cytometric measurement) of CD11c+/MHCII+ lung dendritic cells in vivo. Analysis of cytokines produced by spleen and lung cells, and of antibodies measured in serum and bronchoalveolar lavage fluid, shows that the immunity induced is biased toward a type 1 response (production of IL-12, IFN-gamma, and IgG2a). Furthermore, elafin overexpression protected mice against further challenge with Ad-LacZ, as assessed by antibody levels and neutralization titer, as well as LacZ expression in lung tissue. Thus, the pleiotropic molecule elafin has significant potential in modulating antigen-presenting cell numbers and activity, and could be beneficial in mucosal protective strategies. PMID:16424380

  12. Clearance of low levels of HCV viremia in the absence of a strong adaptive immune response

    Manns Michael P

    2007-06-01

    Full Text Available Abstract Spontaneous clearance of hepatitis C virus (HCV has frequently been associated with the presence of HCV-specific cellular immunity. However, there had been also reports in chimpanzees demonstrating clearance of HCV-viremia in the absence of significant levels of detectable HCV-specific cellular immune responses. We here report seven asymptomatic acute hepatitis C cases with peak HCV-RNA levels between 300 and 100.000 copies/ml who all cleared HCV-RNA spontaneously. Patients were identified by a systematic screening of 1176 consecutive new incoming offenders in a German young offender institution. Four of the seven patients never developed anti-HCV antibodies and had normal ALT levels throughout follow-up. Transient weak HCV-specific CD4+ T cell responses were detectable in five individuals which did not differ in strength and breadth from age- and sex-matched patients with chronic hepatitis C and long-term recovered patients. In contrast, HCV-specific MHC-class-I-tetramer-positive cells were found in 3 of 4 HLA-A2-positive patients. Thus, these cases highlight that clearance of low levels of HCV viremia is possible in the absence of a strong adaptive immune response which might explain the low seroconversion rate after occupational exposure to HCV.

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

    Hernández-Santos, N; Huppler, A R; Peterson, A C; Khader, S A; McKenna, K C; Gaffen, S L

    2013-09-01

    Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by Candida albicans. Despite its prevalence, little is known about C. albicans-specific immunity in the oral mucosa. Vaccines against Candida generate both T helper type 1 (Th1) and Th17 responses, and considerable evidence implicates interleukin (IL)-17 in immunity to OPC. However, IL-17 is also produced by innate immune cells that are remarkably similar to Th17 cells, expressing the same markers and localizing to similar mucosal sites. To date, the relative contribution(s) of Th1, Th17, and innate IL-17-producing cells in OPC have not been clearly defined. Here, we sought to determine the nature and function of adaptive T-cell responses to OPC, using a new recall infection model. Mice subjected to infection and re-challenge with Candida mounted a robust and stable antigen-specific IL-17 response in CD4+ but not CD8+ T cells. There was little evidence for Th1 or Th1/Th17 responses. The Th17 response promoted accelerated fungal clearance, and Th17 cells could confer protection in Rag1-/- mice upon adoptive transfer. Surprisingly, CD4 deficiency did not cause OPC but was instead associated with compensatory IL-17 production by Tc17 and CD3+CD4-CD8- cells. Therefore, classic CD4+Th17 cells protect from OPC but can be compensated by other IL-17-producing cells in CD4-deficient hosts. PMID:23250275

  14. Aircraft Abnormal Conditions Detection, Identification, and Evaluation Using Innate and Adaptive Immune Systems Interaction

    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

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

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

    2015-01-01

    BCG vaccination is associated with a reduced mortality from nonmycobacterial infections. This is likely to be mediated by a combination of innate-immune memory ("trained immunity") and heterologous effects on adaptive immunity. As such, BCG could be used to boost host immunity but not in...... immunocompromised hosts, as it is a live, attenuated vaccine. Therefore, we assessed whether killed γBCG has similar potentiating effects. In an in vitro model of trained immunity, human monocytes were incubated with γBCG for 24 h and restimulated after 6 d. Cytokine production and the role of pattern recognition...... receptors and histone methylation markers were assessed. The in vivo effects of γBCG vaccination were studied in a proof-of-principle trial in 15 healthy volunteers. γBCG induced trained immunity in vitro via the NOD2 receptor pathway and up-regulation of H3K4me3 histone methylation. However, these effects...

  16. SOCS, inflammation and autoimmunity

    Akihiko eYoshimura

    2012-03-01

    Full Text Available Cytokines play essential roles in innate and adaptive immunity. However, excess cytokines or dysregulation of cytokine signaling can cause a variety of diseases, including allergies, autoimmune diseases, inflammation, and cancer. Most cytokines utilize the so-called Janus kinase-signal transducers and activators of transcription (JAK-STAT pathway. This pathway is negatively regulated by various mechanisms including suppressors of cytokine signaling (SOCS proteins. SOCS proteins bind to JAK or cytokine receptors, thereby suppressing further signaling events. Especially, SOCS1 and SOCS3 are strong inhibitors of JAK, because these two contain kinase inhibitory region (KIR at the N-terminus. Studies using conditional knockout mice have shown that SOCS proteins are key physiological as well as pathological regulators of immune homeostasis. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of helper T cell differentiation and functions.

  17. Persistence and Adaptation in Immunity: T Cells Balance the Extent and Thoroughness of Search.

    G Matthew Fricke

    2016-03-01

    Full Text Available Effective search strategies have evolved in many biological systems, including the immune system. T cells are key effectors of the immune response, required for clearance of pathogenic infection. T cell activation requires that T cells encounter antigen-bearing dendritic cells within lymph nodes, thus, T cell search patterns within lymph nodes may be a crucial determinant of how quickly a T cell immune response can be initiated. Previous work suggests that T cell motion in the lymph node is similar to a Brownian random walk, however, no detailed analysis has definitively shown whether T cell movement is consistent with Brownian motion. Here, we provide a precise description of T cell motility in lymph nodes and a computational model that demonstrates how motility impacts T cell search efficiency. We find that both Brownian and Lévy walks fail to capture the complexity of T cell motion. Instead, T cell movement is better described as a correlated random walk with a heavy-tailed distribution of step lengths. Using computer simulations, we identify three distinct factors that contribute to increasing T cell search efficiency: 1 a lognormal distribution of step lengths, 2 motion that is directionally persistent over short time scales, and 3 heterogeneity in movement patterns. Furthermore, we show that T cells move differently in specific frequently visited locations that we call "hotspots" within lymph nodes, suggesting that T cells change their movement in response to the lymph node environment. Our results show that like foraging animals, T cells adapt to environmental cues, suggesting that adaption is a fundamental feature of biological search.

  18. An Act of Balance Between Adaptive and Maladaptive Immunity in Depression: a Role for T Lymphocytes.

    Toben, Catherine; Baune, Bernhard T

    2015-12-01

    Historically the monoaminergic neurotransmitter system, in particular the serotonergic system, was seen as being responsible for the pathophysiology of major depressive disorder (MDD). With the advent of psychoneuroimmunology an important role of the immune system in the interface between the central nervous systems (CNS) and peripheral organ systems has emerged. In addition to the well-characterised neurobiological activities of cytokines, T cell function in the context of depression has been neglected so far. In this review we will investigate the biological roles of T cells in depression. Originally it was thought that the adaptive immune arm including T lymphocytes was excluded from the CNS. It is now clear that peripheral naïve T cells not only carry out continuous surveillance within the brain but also maintain neural plasticity. Furthermore animal studies demonstrate that regulatory T lymphocytes can provide protection against maladaptive behavioural responses associated with depression. Psychogenic stress as a major inducer of depression can lead to transient trafficking of T lymphocytes into the brain stimulating the secretion of certain neurotrophic factors and cytokines. The separate and combined mechanism of CD4 and CD8 T cell activation is likely to determine the response pattern of CNS specific neurokines and neurotrophins. Under chronic stress-induced neuroinflammatory conditions associated with depression, T cell responses may become maladaptive and can be involved in neurodegeneration. Additionally, intracellular adhesion and MHC molecule expression as well as glucocorticoid receptor expression within the brain may play a role in determining T lymphocyte functionality in depression. Taken together, T lymphocyte mechanisms, which confer susceptibility or resilience to MDD, are not yet fully understood. Further insight into the cellular and molecular mechanisms which balance the adaptive and maladaptive roles of T lymphocytes may provide a better

  19. Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice.

    Rebecca Banerjee

    Full Text Available BACKGROUND: Innate neuroimmune dysfunction is a pathobiological feature of amyotrophic lateral sclerosis (ALS. However, links, if any, between disease and adaptive immunity are poorly understood. Thus, the role of T cell immunity in disease was investigated in human G93A superoxide dismutase 1 (SOD1 transgenic (Tg mice and subsequently in ALS patients. METHODS AND FINDINGS: Quantitative and qualitative immune deficits in lymphoid cell and T cell function were seen in G93A-SOD1 Tg mice. Spleens of Tg animals showed reductions in size, weight, lymphocyte numbers, and morphological deficits at terminal stages of disease compared to their wild-type (Wt littermates. Spleen sizes and weights of pre-symptomatic Tg mice were unchanged, but deficits were readily seen in T cell proliferation coincident with increased annexin-V associated apoptosis and necrosis of lymphocytes. These lymphoid deficits paralleled failure of Copolymer-1 (COP-1 immunization to affect longevity. In addition, among CD4(+ T cells in ALS patients, levels of CD45RA(+ (naïve T cells were diminished, while CD45RO(+ (memory T cells were increased compared to age-matched caregivers. In attempts to correct mutant SOD1 associated immune deficits, we reconstituted SOD1 Tg mice with unfractionated naïve lymphocytes or anti-CD3 activated CD4(+CD25(+ T regulatory cells (Treg or CD4(+CD25(- T effector cells (Teff from Wt donor mice. While naive lymphocytes failed to enhance survival, both polyclonal-activated Treg and Teff subsets delayed loss of motor function and extended survival; however, only Treg delayed neurological symptom onset, whereas Teff increased latency between disease onset and entry into late stage. CONCLUSIONS: A profound and progressive immunodeficiency is operative in G93A-SOD1 mice and is linked to T cell dysfunction and the failure to elicit COP-1 neuroprotective immune responses. In preliminary studies T cell deficits were also observed in human ALS. These findings

  20. The Immune Response to Acute Focal Cerebral Ischemia and Associated Post-stroke Immunodepression: A Focused Review

    Famakin, Bolanle M.

    2014-01-01

    It is currently well established that the immune system is activated in response to transient or focal cerebral ischemia. This acute immune activation occurs in response to damage, and injury, to components of the neurovascular unit and is mediated by the innate and adaptive arms of the immune response. The initial immune activation is rapid, occurs via the innate immune response and leads to inflammation. The inflammatory mediators produced during the innate immune response in turn lead to r...

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

    Philipp Schuster

    2011-01-01

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

  2. The adaptive immune system in atopic dermatitis and implications on therapy.

    Roesner, Lennart M; Werfel, Thomas; Heratizadeh, Annice

    2016-07-01

    In atopic dermatitis (AD), the skin inflammation is believed to occur due to a misdirected immune reaction against harmless antigens on the one hand, and to a disturbed skin barrier on the other. In recent years, vast efforts have been made to investigate the relevance and details of the immune response to allergens. Clinically, it was demonstrated for the first time that aeroallergen exposure leads to worsening of AD symptoms. An overexpression of Th2 cytokines has been observed in acute and subacute lesions of AD. The clinical impact of the key Th2 cytokines IL-4 and IL-13 on atopic dermatitis has recently been shown in clinical studies with dupilumab, a monoclonal antibody which blocks the IL-4/IL-13 receptor. In vitro data indicate, however, that the T cell response is not solely Th2-polarized but may lead to heterogeneous cytokine production involving IFN-γ and IL-17 in an allergen-dependent manner. Classical thymus-derived Foxp3 T cells have interestingly been detected in elevated numbers in the circulation of AD patients. Therapeutic approaches with allergen specific immunotherapy aim to induce regulatory T cells of the Tr1 type. The strikingly altered microbiome of AD skin with diminished diversity of bacteria on lesional skin but increases of S. aureus colonization and the sensitization against microbial allergens and homologue self-proteins deserve special attention. For the treatment of itch symptoms, which still represent a challenge in daily practice, promising data have been published on the relevance of the H(histamine)4-receptor and on mediators such as IL-31, TSLP. PMID:26967382

  3. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators

    Serhan, Charles N.; Chiang, Nan; Van Dyke, Thomas E.

    2008-01-01

    Active resolution of acute inflammation is a previously unrecognized interface between innate and adaptive immunity. Once thought to be a passive process, the resolution of inflammation is now shown to involve active biochemical programmes that enable inflamed tissues to return to homeostasis. This Review presents newly uncovered cellular and molecular mechanisms for the resolution of inflammation, revealing key roles for eicosanoids, such as lipoxins, and new families of endogenous chemical ...

  4. Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens

    Holtzman, Michael J.

    2012-01-01

    Research on the pathogenesis of asthma has traditionally concentrated on environmental stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. The focus of this cascade has been the response to allergic stimuli. An alternative scheme suggests that respiratory viruses and the consequent response of the innate immune system also drives the development of asthma as well a...

  5. Developmental minocycline treatment reverses the effects of neonatal immune activation on anxiety- and depression-like behaviors, hippocampal inflammation, and HPA axis activity in adult mice.

    Majidi, Jafar; Kosari-Nasab, Morteza; Salari, Ali-Akbar

    2016-01-01

    Neonatal infection is associated with increased lifetime risk for neuropsychiatric disorders including anxiety and depression, with evidence showing that dysregulation of the hypothalamic-pituitary-adrenal-(HPA)-axis system may be partly responsible. Preclinical and clinical studies demonstrate that minocycline exhibits antidepressant effects through inhibition of microglial activation and anti-inflammatory actions, and of interest is that recent studies suggest that minocycline alleviates the behavioral abnormalities induced by early-life insults. The current study was designed to determine if developmental minocycline treatment attenuates the neonatal immune activation-induced anxiety- and depression-like symptoms and HPA-axis-dysregulation later in life. To this end, neonatal mice were treated to either lipopolysaccharide or saline on postnatal days (PND) 3-5, then dams during lactation (PND 6-20) and male offspring during adolescence (PND 21-40) received oral administration of minocycline or water via regular drinking bottles. Anxiety- and depression-like behaviors, HPA-axis-reactivity (corticosterone), and hippocampal inflammation (TNF-α and IL-1β) after exposure to stress were evaluated. The results indicated that neonatal immune activation resulted in increased anxiety and depression-like symptoms, HPA-axis-hyperactivity, and elevated the levels of TNF-α and IL-1β in the hippocampus in response to stress in adulthood. Interestingly, developmental minocycline treatment significantly reduced the abnormalities induced by neonatal inflammation in adult mice. In addition, minocycline, regardless of postnatal inflammation, did not have any detrimental effects on the above measured parameters. Considering that minocycline is currently under exploration as an alternative or adjunctive therapy for reducing the symptoms of neurological disorders, our findings suggest that minocycline during development can decrease the behavioral abnormalities induced by early

  6. CRISPR/Cas and Cmr modules, mobility and evolution of adaptive immune systems

    Shah, Shiraz Ali; Garrett, Roger Antony

    2011-01-01

    CRISPR/Cas and CRISPR/Cmr immune machineries of archaea and bacteria provide an adaptive and effective defence mechanism directed specifically against viruses and plasmids. Present data suggest that both CRISPR/Cas and Cmr modules can behave like integral genetic elements. They tend to be located...... in the more variable regions of chromosomes and are displaced by genome shuffling mechanisms including transposition. CRISPR loci may be broken up and dispersed in chromosomes by transposons with the potential for creating genetic novelty. Both CRISPR/Cas and Cmr modules appear to exchange readily...... the significant barriers imposed by their differing conjugative, transcriptional and translational mechanisms. There are parallels between the CRISPR crRNAs and eukaryal siRNAs, most notably to germ cell piRNAs which are directed, with the help of effector proteins, to silence or destroy transposons...

  7. Children after Chernobyl: immune cells adaptive changes and stable alterations under low-dose irradiation

    Early changes of immune parameters in children evacuated from 30-km zone were characterized by E-rossette forming cells decrease and E-receptor non-stability in theophylline assay, surface Ig changes. Immunological follow-up of children inhabitants of territories contaminated with radionuclides after Chernobyl accident revealed TCR/CD3, CD4 and MHC CD3+, CD4+, CD57+ subsets, RIL-2, TrT expression and calcium channel activity. PMNC percentage with cortical thymocyte phenotype (CD1+, CD4+8+) was elevated during the first years after the accident and seemed to be of a compensatory origin. Combination of heterogenic activation and suppression subset reactions and changes in fine subset (Th1/Th2) organization were suggested. Adaptive and compensatory reactions were supposed and delayed hypersensitivity reactions increase as well. (author)

  8. Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus

    McSorley, Henry J; O'Gorman, Mary T.; Blair, Natalie; Sutherland, Tara E.; Filbey, Kara J.; Maizels, Rick M.

    2012-01-01

    Allergic asthma is less prevalent in countries with parasitic helminth infections, and mice infected with parasites such as Heligmosomoides polygyrus are protected from allergic airway inflammation. To establish whether suppression of allergy could be mediated by soluble products of this helminth, we tested H. polygyrus excretory-secretory (HES) material for its ability to impair allergic inflammation. When HES was added to sensitising doses of ovalbumin, the subsequent allergic airway respon...

  9. The innate and adaptive immune response induced by alveolar macrophages exposed to ambient particulate matter

    Emerging epidemiological evidence suggests that exposure to particulate matter (PM) air pollution increases the risk of cardiovascular events but the exact mechanism by which PM has adverse effects is still unclear. Alveolar macrophages (AM) play a major role in clearing and processing inhaled PM. This comprehensive review of research findings on immunological interactions between AM and PM provides potential pathophysiological pathways that interconnect PM exposure with adverse cardiovascular effects. Coarse particles (10 μm or less, PM10) induce innate immune responses via endotoxin-toll-like receptor (TLR) 4 pathway while fine (2.5 μm or less, PM2.5) and ultrafine particles (0.1 μm or less, UFP) induce via reactive oxygen species generation by transition metals and/or polyaromatic hydrocarbons. The innate immune responses are characterized by activation of transcription factors [nuclear factor (NF)-κB and activator protein-1] and the downstream proinflammatory cytokine [interleukin (IL)-1β, IL-6, and tumor necrosis factor-α] production. In addition to the conventional opsonin-dependent phagocytosis by AM, PM can also be endocytosed by an opsonin-independent pathway via scavenger receptors. Activation of scavenger receptors negatively regulates the TLR4-NF-κB pathway. Internalized particles are subsequently subjected to adaptive immunity involving major histocompatibility complex class II (MHC II) expression, recruitment of costimulatory molecules, and the modulation of the T helper (Th) responses. AM show atypical antigen presenting cell maturation in which phagocytic activity decreases while both MHC II and costimulatory molecules remain unaltered. PM drives AM towards a Th1 profile but secondary responses in a Th1- or Th-2 up-regulated milieu drive the response in favor of a Th2 profile.

  10. The innate and adaptive immune response induced by alveolar macrophages exposed to ambient particulate matter

    Miyata, Ryohei; Eeden, Stephan F. van, E-mail: Stephan.vanEeden@hli.ubc.ca

    2011-12-15

    Emerging epidemiological evidence suggests that exposure to particulate matter (PM) air pollution increases the risk of cardiovascular events but the exact mechanism by which PM has adverse effects is still unclear. Alveolar macrophages (AM) play a major role in clearing and processing inhaled PM. This comprehensive review of research findings on immunological interactions between AM and PM provides potential pathophysiological pathways that interconnect PM exposure with adverse cardiovascular effects. Coarse particles (10 {mu}m or less, PM{sub 10}) induce innate immune responses via endotoxin-toll-like receptor (TLR) 4 pathway while fine (2.5 {mu}m or less, PM{sub 2.5}) and ultrafine particles (0.1 {mu}m or less, UFP) induce via reactive oxygen species generation by transition metals and/or polyaromatic hydrocarbons. The innate immune responses are characterized by activation of transcription factors [nuclear factor (NF)-{kappa}B and activator protein-1] and the downstream proinflammatory cytokine [interleukin (IL)-1{beta}, IL-6, and tumor necrosis factor-{alpha}] production. In addition to the conventional opsonin-dependent phagocytosis by AM, PM can also be endocytosed by an opsonin-independent pathway via scavenger receptors. Activation of scavenger receptors negatively regulates the TLR4-NF-{kappa}B pathway. Internalized particles are subsequently subjected to adaptive immunity involving major histocompatibility complex class II (MHC II) expression, recruitment of costimulatory molecules, and the modulation of the T helper (Th) responses. AM show atypical antigen presenting cell maturation in which phagocytic activity decreases while both MHC II and costimulatory molecules remain unaltered. PM drives AM towards a Th1 profile but secondary responses in a Th1- or Th-2 up-regulated milieu drive the response in favor of a Th2 profile.

  11. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis.

    Inoue, Shigeaki; Unsinger, Jacqueline; Davis, Christopher G; Muenzer, Jared T; Ferguson, Thomas A; Chang, Katherine; Osborne, Dale F; Clark, Andrew T; Coopersmith, Craig M; McDunn, Jonathan E; Hotchkiss, Richard S

    2010-02-01

    IL-15 is a pluripotent antiapoptotic cytokine that signals to cells of both the innate and adaptive immune system and is regarded as a highly promising immunomodulatory agent in cancer therapy. Sepsis is a lethal condition in which apoptosis-induced depletion of immune cells and subsequent immunosuppression are thought to contribute to morbidity and mortality. This study tested the ability of IL-15 to block apoptosis, prevent immunosuppression, and improve survival in sepsis. Mice were made septic using cecal ligation and puncture or Pseudomonas aeruginosa pneumonia. The experiments comprised a 2 x 2 full factorial design with surgical sepsis versus sham and IL-15 versus vehicle. In addition to survival studies, splenic cellularity, canonical markers of activation and proliferation, intracellular pro- and antiapoptotic Bcl-2 family protein expression, and markers of immune cell apoptosis were evaluated by flow cytometry. Cytokine production was examined both in plasma of treated mice and splenocytes that were stimulated ex vivo. IL-15 blocked sepsis-induced apoptosis of NK cells, dendritic cells, and CD8 T cells. IL-15 also decreased sepsis-induced gut epithelial apoptosis. IL-15 therapy increased the abundance of antiapoptotic Bcl-2 while decreasing proapoptotic Bim and PUMA. IL-15 increased both circulating IFN-gamma, as well as the percentage of NK cells that produced IFN-gamma. Finally, IL-15 increased survival in both cecal ligation and puncture and P. aeruginosa pneumonia. In conclusion, IL-15 prevents two immunopathologic hallmarks of sepsis, namely, apoptosis and immunosuppression, and improves survival in two different models of sepsis. IL-15 represents a potentially novel therapy of this highly lethal disorder. PMID:20026737

  12. Active chinese mistletoe lectin-55 enhances colon cancer surveillance through regulating innate and adaptive immune responses

    Yan-Hui Ma; Wei-Zhi Cheng; Fang Gong; An-Lun Ma; Qi-Wen Yu; Ji-Ying Zhang; Chao-Ying Hu; Xue-Hua Chen; Dong-Qing Zhang

    2008-01-01

    AIM:To investigate the potential role of Active Chinese mistletoe lectin-55 (ACML-55) in tumor immune surveillance.METHODS:In this study,an experimental model was established by hypodermic inoculating the colon cancer cell line CT26 (5×105 cells) into BALB/c mice.The experimental treatment was orally administered with ACML-55 or PBS,followed by the inoculation of colon cancer cell line CT26.Intracellular cytokine staining was used to detect IFN-y production by tumor antigen specific CD8+ T cells.FACS analysis was employed to profile composition and activation of CD4+,CD8+,γδ T and NK cells.RESULTS:Our results showed,compared to PBS treated mice,ACML-55 treatment significantly delayed colon cancer development in colon cancer-bearing Balb/c mice in vivo.Treatment with ACML-55 enhanced both Ag specific activation and proliferation of CD4+ and CD8+ T cells,and increased the number of tumor Ag specific CD8+ T cells,it was more important to increase the frequency of tumor Ag specific IFN-γ producing-CD8+ T cells.Interestingly,ACML-55 treatment also showed increased cell number of NK,and γδT cells,indicating the role of ACML-55 in activation of innate lymphooltes.CONCLUSION:Our results demonstrate that ACML-55therapy can enhance function in immune surveillance in colon cancer-bearing mice through regulating both innate and adaptive immune responses.

  13. The role of idiotypic interactions in the adaptive immune system: a belief-propagation approach

    Bartolucci, Silvia; Mozeika, Alexander; Annibale, Alessia

    2016-08-01

    In this work we use belief-propagation techniques to study the equilibrium behaviour of a minimal model for the immune system comprising interacting T and B clones. We investigate the effect of the so-called idiotypic interactions among complementary B clones on the system’s activation. Our results show that B–B interactions increase the system’s resilience to noise, making clonal activation more stable, while increasing the cross-talk between different clones. We derive analytically the noise level at which a B clone gets activated, in the absence of cross-talk, and find that this increases with the strength of idiotypic interactions and with the number of T cells sending signals to the B clones. We also derive, analytically and numerically, via population dynamics, the critical line where clonal cross-talk arises. Our approach allows us to derive the B clone size distribution, which can be experimentally measured and gives important information about the adaptive immune system response to antigens and vaccination.

  14. Unusual association of amyotrophic lateral sclerosis and myasthenia gravis: A dysregulation of the adaptive immune system?

    Del Mar Amador, Maria; Vandenberghe, Nadia; Berhoune, Nawel; Camdessanché, Jean-Philippe; Gronier, Sophie; Delmont, Emilien; Desnuelle, Claude; Cintas, Pascal; Pittion, Sophie; Louis, Sarah; Demeret, Sophie; Lenglet, Timothée; Meininger, Vincent; Salachas, François; Pradat, Pierre-François; Bruneteau, Gaëlle

    2016-06-01

    Myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions that has been associated with a small increased risk of amyotrophic lateral sclerosis (ALS). Here, we describe a retrospective series of seven cases with a concomitant diagnosis of ALS and myasthenia gravis, collected among the 18 French reference centers for ALS in a twelve year period. After careful review, only six patients strictly met the diagnostic criteria for both ALS and myasthenia gravis. In these patients, limb onset of ALS was reported in five (83%) cases. Localization of myasthenia gravis initial symptoms was ocular in three (50%) cases, generalized in two (33%) and bulbar in one (17%). Median delay between onset of the two conditions was 19 months (6-319 months). Anti-acetylcholine receptor antibodies testing was positive in all cases. All patients were treated with riluzole and one had an associated immune-mediated disease. In the one last ALS case, the final diagnosis was false-positivity for anti-acetylcholine receptor antibodies. The co-occurrence of ALS and myasthenia gravis is rare and requires strict diagnostic criteria. Its demonstration needs thoughtful interpretation of electrophysiological results and exclusion of false positivity for myasthenia gravis antibody testing in some ALS cases. This association may be triggered by a dysfunction of adaptive immunity. PMID:27102004

  15. Fel d 1-airway inflammation prevention and treatment by co-immunization vaccine via induction of CD4+CD25-Foxp3+ Treg cells

    Pei, Yechun; Geng, Shuang; Liu, Lin; Yan, Fengxiang; Hong GUAN; Hou, Jian; Chen, Yongfu; Wang, Bin; An, Xiaorong

    2013-01-01

    Pet allergens are major causes for asthma and allergic rhinitis. Fel d 1 protein, a key pet allergen from domestic cat, can sensitize host and trigger asthma attack. In this study, we report that co-immunization with recombinant Fel d 1 protein (rFel d 1) plus plasmid DNA that contains Fe1 d 1 gene was effective in preventing and treating the natural Fel d 1 (nFel d 1) induced allergic airway inflammation in mice. A population of T regulatory cells (iTreg) exhibiting a CD4+CD25-Foxp3+ phenoty...

  16. Self-adjuvanted mRNA vaccines induce local innate immune responses that lead to a potent and boostable adaptive immunity.

    Kowalczyk, Aleksandra; Doener, Fatma; Zanzinger, Kai; Noth, Janine; Baumhof, Patrick; Fotin-Mleczek, Mariola; Heidenreich, Regina

    2016-07-19

    mRNA represents a new platform for the development of therapeutic and prophylactic vaccines with high flexibility with respect to production and application. We have previously shown that our two component self-adjuvanted mRNA-based vaccines (termed RNActive® vaccines) induce balanced immune responses comprising both humoral and cellular effector as well as memory responses. Here, we evaluated the early events upon intradermal application to gain more detailed insights into the underlying mode of action of our mRNA-based vaccine. We showed that the vaccine is taken up in the skin by both non-leukocytic and leukocytic cells, the latter being mostly represented by antigen presenting cells (APCs). mRNA was then transported to the draining lymph nodes (dLNs) by migratory dendritic cells. Moreover, the encoded protein was expressed and efficiently presented by APCs within the dLNs as shown by T cell proliferation and immune cell activation, followed by the induction of the adaptive immunity. Importantly, the immunostimulation was limited to the injection site and lymphoid organs as no proinflammatory cytokines were detected in the sera of the immunized mice indicating a favorable safety profile of the mRNA-based vaccines. Notably, a substantial boostability of the immune responses was observed, indicating that mRNA can be used effectively in repetitive immunization schedules. The evaluation of the immunostimulation following prime and boost vaccination revealed no signs of exhaustion as demonstrated by comparable levels of cytokine production at the injection site and immune cell activation within dLNs. In summary, our data provide mechanistic insight into the mode of action and a rational for the use of mRNA-based vaccines as a promising immunization platform. PMID:27269061

  17. Innate immunity in the pathogenesis of psoriasis.

    Sweeney, Cheryl M

    2011-12-01

    Psoriasis is a common, immune-mediated inflammatory skin disorder. T helper(h)1 and Th17 lymphocytes contribute to the pathogenesis of psoriasis through the release of inflammatory cytokines that promote further recruitment of immune cells, keratinocyte proliferation and sustained inflammation. The innate immune system is the first line of defence against infection and plays a crucial role in the initiation of the adaptive immune response. The presence of innate immune cells and their products in psoriatic skin plaques suggests a role for innate immunity in this disease. In addition, the innate immune system can direct the development of pathogenic Th cells in psoriasis. In this article, we will summarise the role of the innate immune system in psoriasis with particular emphasis on the role of cytokines, signalling pathways and cells of the innate immune system.

  18. NEW EMBO MEMBER’S REVIEW: Dendritic cell regulation of immune responses: a new role for interleukin 2 at the intersection of innate and adaptive immunity

    Granucci, Francesca; Zanoni, Ivan; Feau, Sonia; Ricciardi-Castagnoli, Paola

    2003-01-01

    Dendritic cells are professional antigen-presenting cells able to initiate innate and adaptive immune responses against invading pathogens. In response to external stimuli dendritic cells undergo a complete genetic reprogramming that allows them to become, soon after activation, natural killer cell activators and subsequently T cell stimulators. The recent observation that dendritic cells produce interleukin 2 following microbial stimulation opens new possibilities for understanding the effic...

  19. Age-Dependent Cell Trafficking Defects in Draining Lymph Nodes Impair Adaptive Immunity and Control of West Nile Virus Infection.

    Justin M Richner

    2015-07-01

    Full Text Available Impaired immune responses in the elderly lead to reduced vaccine efficacy and increased susceptibility to viral infections. Although several groups have documented age-dependent defects in adaptive immune priming, the deficits that occur prior to antigen encounter remain largely unexplored. Herein, we identify novel mechanisms for compromised adaptive immunity that occurs with aging in the context of infection with West Nile virus (WNV, an encephalitic flavivirus that preferentially causes disease in the elderly. An impaired IgM and IgG response and enhanced vulnerability to WNV infection during aging was linked to delayed germinal center formation in the draining lymph node (DLN. Adoptive transfer studies and two-photon intravital microscopy revealed a decreased trafficking capacity of donor naïve CD4+ T cells from old mice, which manifested as impaired T cell diapedesis at high endothelial venules and reduced cell motility within DLN prior to antigen encounter. Furthermore, leukocyte accumulation in the DLN within the first few days of WNV infection or antigen-adjuvant administration was diminished more generally in old mice and associated with a second aging-related defect in local cytokine and chemokine production. Thus, age-dependent cell-intrinsic and environmental defects in the DLN result in delayed immune cell recruitment and antigen recognition. These deficits compromise priming of early adaptive immune responses and likely contribute to the susceptibility of old animals to acute WNV infection.

  20. Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function

    Phillips R

    2006-04-01

    Full Text Available Abstract Background Dendritic cells (DCs are central to the initiation and regulation of the adaptive immune response during infection. Modulation of DC function may therefore allow evasion of the immune system by pathogens. Significant depression of the host's systemic immune response to both concurrent infections and heterologous vaccines has been observed during malaria infection, but the mechanisms underlying this immune hyporesponsiveness are controversial. Results Here, we demonstrate that the blood stages of malaria infection induce a failure of DC function in vitro and in vivo, causing suboptimal activation of T cells involved in heterologous immune responses. This effect on T-cell activation can be transferred to uninfected recipients by DCs isolated from infected mice. Significantly, T cells activated by these DCs subsequently lack effector function, as demonstrated by a failure to migrate to lymphoid-organ follicles, resulting in an absence of B-cell responses to heterologous antigens. Fractionation studies show that hemozoin, rather than infected erythrocyte (red blood cell membranes, reproduces the effect of intact infected red blood cells on DCs. Furthermore, hemozoin-containing DCs could be identified in T-cell areas of the spleen in vivo. Conclusion Plasmodium infection inhibits the induction of adaptive immunity to heterologous antigens by modulating DC function, providing a potential explanation for epidemiological studies linking endemic malaria with secondary infections and reduced vaccine efficacy.

  1. Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses.

    Rajani, Karishma; Parrish, Christopher; Kottke, Timothy; Thompson, Jill; Zaidi, Shane; Ilett, Liz; Shim, Kevin G; Diaz, Rosa-Maria; Pandha, Hardev; Harrington, Kevin; Coffey, Matt; Melcher, Alan; Vile, Richard

    2016-02-01

    Oncolytic reovirus can be delivered both systemically and intratumorally, in both preclinical models and in early phase clinical trials. Reovirus has direct oncolytic activity against a variety of tumor types and antitumor activity is directly associated with immune activation by virus replication in tumors. Immune mechanisms of therapy include both innate immune activation against virally infected tumor cells, and the generation of adaptive antitumor immune responses as a result of in vivo priming against tumor-associated antigens. We tested the combination of local oncolytic reovirus therapy with systemic immune checkpoint inhibition. We show that treatment of subcutaneous B16 melanomas with a combination of intravenous (i.v.) anti-PD-1 antibody and intratumoral (i.t.) reovirus significantly enhanced survival of mice compared to i.t. reovirus (P cells to kill reovirus-infected tumor cells, reduced T(reg) activity, and increased the adaptive CD8(+) T-cell-dependent antitumor T-cell response. PD-1 blockade also enhanced the antiviral immune response but through effector mechanisms which overlapped with but also differed from those affecting the antitumor response. Therefore, combination with checkpoint inhibition represents a readily translatable next step in the clinical development of reovirus viroimmunotherapy. PMID:26310630

  2. STSV2 as a Model Crenarchaeal Virus for Studying Virus-Host Interactions and CRISPR-Cas Adaptive Immunity

    León Sobrino, Carlos

    archaea harbour their own viruses, which constitute an extraordinarily diverse group with exotic morphologies and unique features. Prokaryotes possess a variety of defence mechanisms. The CRISPR-Cas adaptive immune system is of great importance for archaea –84% of them possess it, compared to 45% for...... generate immune memory by inserting in its own genome short invader-derived DNA fragments forming a database –the CRISPR locus. Little was known about this system until recent years, and the generation of immune memory has been the most elusive step. In this work, the interactions of the spindle......-shaped monocaudavirus STSV2 and its host Sulfolobus islandicus REY15A were studied. This interaction produced, after several days, de novo CRISPR adaptation – that is, without any previous memory that can act as a trigger. We employed transcriptome sequencing to characterise the long-term progression of this...

  3. Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens.

    Holtzman, Michael J

    2012-08-01

    Research on the pathogenesis of asthma has traditionally concentrated on environmental stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. The focus of this cascade has been the response to allergic stimuli. An alternative scheme suggests that respiratory viruses and the consequent response of the innate immune system also drives the development of asthma as well as related inflammatory diseases. This conceptual shift raises the possibility that sentinel cells such as airway epithelial cells, DCs, NKT cells, innate lymphoid cells, and macrophages also represent critical components of asthma pathogenesis as well as new targets for therapeutic discovery. A particular challenge will be to understand and balance the innate as well as the adaptive immune responses to defend the host against acute infection as well as chronic inflammatory disease. PMID:22850884

  4. Acrolein exposure suppresses antigen-induced pulmonary inflammation

    Spiess, Page C; Kasahara, David; Habibovic, Aida; Hristova, Milena; Randall, Matthew J.; Poynter, Matthew E.; van der Vliet, Albert

    2013-01-01

    Background: Adverse health effects of tobacco smoke arise partly from its influence on innate and adaptive immune responses, leading to impaired innate immunity and host defense. The impact of smoking on allergic asthma remains unclear, with various reports demonstrating that cigarette smoke enhances asthma development but can also suppress allergic airway inflammation. Based on our previous findings that immunosuppressive effects of smoking may be largely attributed to one of its main reacti...

  5. Toward a molecular understanding of adaptive immunity:A chronology, Part II

    Kendall A Smith

    2012-11-01

    Full Text Available By 1980 it was obvious that to more fully understand adaptive immunity, one needed to somehow reduce the tremendous complexity of antigen recognition by T cell populations. Thus, there were two developments that resulted in a paradigm shift in immunology, one being the generation of monoclonal antibodies, and the other the development of monoclonal functional antigen-specific T cell lines. For the first time, the cellular reagents became available to ask new questions as to how individual cells comprising the complex cell populations recognize and respond to changes in their molecular environments. The first successful generation of monoclonal T cells depended upon the understanding that antigen renders cells responsive to the antigen non-specific T cell growth factor that came to be termed interleukin-2 (IL-2, which could then be used in propagating large numbers of the progeny of single cells, which in turn could then be used for molecular analyses. Monoclonal functional human T cells were used to immunize mice to generate clone-specific (clonotypic monoclonal antibodies, which then permitted the first biochemical characterizations of the antigen recognition elements of the T cell antigen receptor complex. Moreover, the use of monoclonal cytolytic and helper/inducer human T cell clones essentially proved that the T cell-specific molecules T4 and T8 functioned as accessory molecules in antigen recognition by defining MHC class II or class I restriction respectively. As well, the expression of the T3 molecules, found to be common to all T cells, were shown further to be obligatory for functional antigen-specific T cell signaling. The monoclonal IL-2-dependent T cells were also instrumental in the isolation and purification of the IL-2 molecule to homogeneity, the first interleukin molecule to be identified and characterized. These advances then led to the generation of pure radiolabeled IL-2 molecules that were used to identify the first

  6. The Mushroom Agaricus blazei Murill Elicits Medicinal Effects on Tumor, Infection, Allergy, and Inflammation through Its Modulation of Innate Immunity and Amelioration of Th1/Th2 Imbalance and Inflammation

    Geir Hetland

    2011-01-01

    Full Text Available The medicinal mushroom Agaricus blazei Murill from the Brazilian rain forest has been used in traditional medicine and as health food for the prevention of a range of diseases, including infection, allergy, and cancer. Other scientists and we have examined whether there is scientific evidence behind such postulations. Agaricus blazei M is rich in the immunomodulating polysaccharides, β-glucans, and has been shown to have antitumor, anti-infection, and antiallergic/-asthmatic properties in mouse models, in addition to anti-inflammatory effects in inflammatory bowel disease patients. These effects are mediated through the mushroom's stimulation of innate immune cells, such as monocytes, NK cells, and dendritic cells, and the amelioration of a skewed Th1/Th2 balance and inflammation.

  7. ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK.

    Filippov, Sergey; Pinkosky, Stephen L; Lister, Richard J; Pawloski, Catherine; Hanselman, Jeffrey C; Cramer, Clay T; Srivastava, Rai Ajit K; Hurley, Timothy R; Bradshaw, Cheryl D; Spahr, Mark A; Newton, Roger S

    2013-08-01

    ETC-1002 is an investigational drug currently in Phase 2 development for treatment of dyslipidemia and other cardiometabolic risk factors. In dyslipidemic subjects, ETC-1002 not only reduces plasma LDL cholesterol but also significantly attenuates levels of hsCRP, a clinical biomarker of inflammation. Anti-inflammatory properties of ETC-1002 were further investigated in primary human monocyte-derived macrophages and in in vivo models of inflammation. In cells treated with ETC-1002, increased levels of AMP-activated protein kinase (AMPK) phosphorylation coincided with reduced activity of MAP kinases and decreased production of proinflammatory cytokines and chemokines. AMPK phosphorylation and inhibitory effects of ETC-1002 on soluble mediators of inflammation were significantly abrogated by siRNA-mediated silencing of macrophage liver kinase B1 (LKB1), indicating that ETC-1002 activates AMPK and exerts its anti-inflammatory effects via an LKB1-dependent mechanism. In vivo, ETC-1002 suppressed thioglycollate-induced homing of leukocytes into mouse peritoneal cavity. Similarly, in a mouse model of diet-induced obesity, ETC-1002 restored adipose AMPK activity, reduced JNK phosphorylation, and diminished expression of macrophage-specific marker 4F/80. These data were consistent with decreased epididymal fat-pad mass and interleukin (IL)-6 release by inflamed adipose tissue. Thus, ETC-1002 may provide further clinical benefits for patients with cardiometabolic risk factors by reducing systemic inflammation linked to insulin resistance and vascular complications of metabolic syndrome. PMID:23709692

  8. Heme oxygenase-1 exerts a protective role in ovalbumin-induced neutrophilic airway inflammation by inhibiting Th17 cell-mediated immune response.

    Zhang, Yanjie; Zhang, Liya; Wu, Jinhong; Di, Caixia; Xia, Zhenwei

    2013-11-29

    Allergic asthma is conventionally considered as a Th2 immune response characterized by eosinophilic inflammation. Recent investigations revealed that Th17 cells play an important role in the pathogenesis of non-eosinophilic asthma (NEA), resulting in steroid-resistant neutrophilic airway inflammation. Heme oxygenase-1 (HO-1) has anti-inflammation, anti-oxidation, and anti-apoptosis functions. However, its role in NEA is still unclear. Here, we explore the role of HO-1 in a mouse model of NEA. HO-1 inducer hemin or HO-1 inhibitor tin protoporphyrin IX was injected intraperitoneally into ovalbumin-challenged DO11.10 mice. Small interfering RNA (siRNA) was delivered into mice to knock down HO-1 expression. The results show that induction of HO-1 by hemin attenuated airway inflammation and decreased neutrophil infiltration in bronchial alveolar lavage fluid and was accompanied by a lower proportion of Th17 cells in mediastinal lymph nodes and spleen. More importantly, induction of HO-1 down-regulated Th17-related transcription factor retinoic acid-related orphan receptor γt (RORγt) expression and decreased IL-17A levels, all of which correlated with a decrease in phosphorylated STAT3 (p-STAT3) level and inhibition of Th17 cell differentiation. Consistently, the above events could be reversed by tin protoporphyrin IX. Also, HO-1 siRNA transfection abolished the effect of hemin induced HO-1 in vivo. Meanwhile, the hemin treatment promoted the level of Foxp3 expression and enhanced the proportion of regulatory T cells (Tregs). Collectively, our findings indicate that HO-1 exhibits anti-inflammatory activity in the mouse model of NEA via inhibition of the p-STAT3-RORγt pathway, regulating kinetics of RORγt and Foxp3 expression, thus providing a possible novel therapeutic target in asthmatic patients. PMID:24097973

  9. Points of control exerted along the macrophage-endothelial cell-polymorphonuclear neutrophil axis by PECAM-1 in the innate immune response of acute colonic inflammation.

    Sugimoto, Naohito; Rui, Tao; Yang, Min; Bharwani, Sulaiman; Handa, Osamu; Yoshida, Norimasa; Yoshikawa, Toshikazu; Kvietys, Peter R

    2008-08-01

    PECAM-1 is expressed on endothelial cells and leukocytes. Its extracellular domain has been implicated in leukocyte diapedesis. In this study, we used PECAM-1(-/-) mice and relevant cells derived from them to assess the role of PECAM-1 in an experimental model of acute colonic inflammation with a predominant innate immune response, i.e., 2,4,6-trinitrobenzine sulfonic acid (TNBS). Using chimeric approaches, we addressed the points of control exerted by PECAM-1 along the macrophage-endothelial cell-polymorphonuclear neutrophil (PMN) axis. In vivo, TNBS-induced colitis was ameliorated in PECAM-1(-/-) mice, an event attributed to PECAM-1 on hematopoietic cells rather than to PECAM-1 on endothelial cells. The in vivo innate immune response was mimicked in vitro by using a construct of the vascular-interstitial interface, i.e., PMN transendothelial migration was induced by colonic lavage fluid (CLF) from TNBS mice or macrophages (MPhi) challenged with CLF. Using the construct, we confirmed that endothelial cell PECAM-1 does not play a role in PMN transendothelial migration. Although MPhi activation (NF-kappaB nuclear binding) and function (keratinocyte-derived chemokine production) induced by CLF was diminished in PECAM-1(-/-) MPhi, this did not affect their ability to promote PMN transendothelial migration. By contrast, PECAM-1(-/-) PMN did not adhere to or migrate across endothelial cell monolayers in response to CLF. Further, as compared with PECAM-1(+/+) PMN, PECAM-1(-/-) PMN were less effective in orientating their CXCR2 receptors (polarization) in the direction of a chemotactic gradient. Collectively, our findings indicate that PECAM-1 modulation of PMN function (at a step before diapedesis) most likely contributes to the inflammation in a colitis model with a strong innate immune component. PMID:18641353

  10. Platelet-Activating Factor Is Crucial in Psoralen and Ultraviolet A-Induced Immune Suppression, Inflammation, and Apoptosis

    Wolf, Peter; Nghiem, Dat X.; Walterscheid, Jeffrey P.; Byrne, Scott; Matsumura, Yumi; Matsumura, Yasuhiro; Bucana, Cora; Ananthaswamy, Honnavara N.; Ullrich, Stephen E.

    2006-01-01

    Psoralen plus UVA (PUVA) is used as a very effective treatment modality for various diseases, including psoriasis and cutaneous T-cell lymphoma. PUVA-induced immune suppression and/or apoptosis are thought to be responsible for the therapeutic action. However, the molecular mechanisms by which PUVA acts are not well understood. We have previously identified platelet-activating factor (PAF), a potent phospholipid mediator, as a crucial substance triggering ultraviolet B radiation-induced immun...

  11. Genotype-by-environment interactions and adaptation to local temperature affect immunity and fecundity in Drosophila melanogaster.

    Brian P Lazzaro

    2008-03-01

    Full Text Available Natural populations of most organisms harbor substantial genetic variation for resistance to infection. The continued existence of such variation is unexpected under simple evolutionary models that either posit direct and continuous natural selection on the immune system or an evolved life history "balance" between immunity and other fitness traits in a constant environment. However, both local adaptation to heterogeneous environments and genotype-by-environment interactions can maintain genetic variation in a species. In this study, we test Drosophila melanogaster genotypes sampled from tropical Africa, temperate northeastern North America, and semi-tropical southeastern North America for resistance to bacterial infection and fecundity at three different environmental temperatures. Environmental temperature had absolute effects on all traits, but there were also marked genotype-by-environment interactions that may limit the global efficiency of natural selection on both traits. African flies performed more poorly than North American flies in both immunity and fecundity at the lowest temperature, but not at the higher temperatures, suggesting that the African population is maladapted to low temperature. In contrast, there was no evidence for clinal variation driven by thermal adaptation within North America for either trait. Resistance to infection and reproductive success were generally uncorrelated across genotypes, so this study finds no evidence for a fitness tradeoff between immunity and fecundity under the conditions tested. Both local adaptation to geographically heterogeneous environments and genotype-by-environment interactions may explain the persistence of genetic variation for resistance to infection in natural populations.

  12. Structural basis of evasion of cellular adaptive immunity by HIV-1 Nef

    Jia, Xiaofei; Singh, Rajendra; Homann, Stefanie; Yang, Haitao; Guatelli, John; Xiong, Yong (Yale); (VA); (UCSD)

    2012-10-24

    The HIV-1 protein Nef inhibits antigen presentation by class I major histocompatibility complex (MHC-I). We determined the mechanism of this activity by solving the crystal structure of a protein complex comprising Nef, the MHC-I cytoplasmic domain (MHC-I CD) and the {mu}1 subunit of the clathrin adaptor protein complex 1. A ternary, cooperative interaction clamps the MHC-I CD into a narrow binding groove at the Nef-{mu}1 interface, which encompasses the cargo-recognition site of {mu}1 and the proline-rich strand of Nef. The Nef C terminus induces a previously unobserved conformational change in {mu}1, whereas the N terminus binds the Nef core to position it optimally for complex formation. Positively charged patches on {mu}1 recognize acidic clusters in Nef and MHC-I. The structure shows how Nef functions as a clathrin-associated sorting protein to alter the specificity of host membrane trafficking and enable viral evasion of adaptive immunity.

  13. Differential effects of NOX4 and NOX1 on immune cell-mediated inflammation in the aortic sinus of diabetic ApoE-/- mice.

    Di Marco, Elyse; Gray, Stephen P; Chew, Phyllis; Kennedy, Kit; Cooper, Mark E; Schmidt, Harald H H W; Jandeleit-Dahm, Karin A M

    2016-08-01

    Oxidative stress and inflammation are central mediators of atherosclerosis particularly in the context of diabetes. The potential interactions between the major producers of vascular reactive oxygen species (ROS), NADPH oxidase (NOX) enzymes and immune-inflammatory processes remain to be fully elucidated. In the present study we investigated the roles of the NADPH oxidase subunit isoforms, NOX4 and NOX1, in immune cell activation and recruitment to the aortic sinus atherosclerotic plaque in diabetic ApoE(-/-) mice. Plaque area analysis showed that NOX4- and NOX1-derived ROS contribute to atherosclerosis in the aortic sinus following 10 weeks of diabetes. Immunohistochemical staining of the plaques revealed that NOX4-derived ROS regulate T-cell recruitment. In addition, NOX4-deficient mice showed a reduction in activated CD4(+) T-cells in the draining lymph nodes of the aortic sinus coupled with reduced pro-inflammatory gene expression in the aortic sinus. Conversely, NOX1-derived ROS appeared to play a more important role in macrophage accumulation. These findings demonstrate distinct roles for NOX4 and NOX1 in immune-inflammatory responses that drive atherosclerosis in the aortic sinus of diabetic mice. PMID:27190136

  14. Effects of Lipoic Acid on Immune Function, the Antioxidant Defense System, and Inflammation-Related Genes Expression of Broiler Chickens Fed Aflatoxin Contaminated Diets

    Yan Li

    2014-04-01

    Full Text Available This study was designed to evaluate the effect of low level of Aflatoxin B1 (AFB1 on oxidative stress, immune reaction and inflammation response and the possible ameliorating effects of dietary alpha-lipoic acid (α-LA in broilers. Birds were randomly allocated into three groups and assigned to receive different diets: basal diet, diet containing 74 μg/kg AFB1, and 300 mg/kg α-LA supplementation in diet containing 74 μg/kg AFB1 for three weeks. The results showed that the serum levels of malondialdehyde, tumor necrosis factor alpha (TNFα and interferon gamma (IFNγ in the AFB1-treated group were significantly increased than the control group. In addition, the increased expressions of interleukin 6 (IL6, TNFα and IFNγ were observed in birds exposed to the AFB1-contaminated diet. These degenerative changes were inhibited by α-LA-supplement. The activities of total superoxide dismutase and glutathione peroxidase, the levels of humoral immunity, and the expressions of nuclear factor-κB p65 and heme oxygenase-1, however, were not affected by AFB1. The results suggest that α-LA alleviates AFB1 induced oxidative stress and immune changes and modulates the inflammatory response at least partly through changes in the expression of proinflammatory cytokines of spleen such as IL6 and TNFα in broiler chickens.

  15. Immune Response in Thyroid Cancer: Widening the Boundaries

    Laura Sterian Ward

    2014-01-01

    The association between thyroid cancer and thyroid inflammation has been repeatedly reported and highly debated in the literature. In fact, both molecular and epidemiological data suggest that these diseases are closely related and this association reinforces that the immune system is important for thyroid cancer progression. Innate immunity is the first line of defensive response. Unlike innate immune responses, adaptive responses are highly specific to the particular antigen that induced th...

  16. A possible link between loading, inflammation and healing: Immune cell populations during tendon healing in the rat.

    Blomgran, Parmis; Blomgran, Robert; Ernerudh, Jan; Aspenberg, Per

    2016-01-01

    Loading influences tendon healing, and so does inflammation. We hypothesized that the two are connected. 48 rats underwent Achilles tendon transection. Half of the rats received Botox injections into calf muscles to reduce mechanical loading. Cells from the regenerating tissue were analyzed by flow cytometry. In the loaded group, the regenerating tissue contained 83% leukocytes (CD45(+)) day 1, and 23% day 10. The M1/M2 macrophage ratio (CCR7/CD206) peaked at day 3, while T helper (CD3(+)CD4(+)) and Treg cells (CD25(+) Foxp3(+)) increased over time. With Botox, markers associated with down-regulation of inflammation were more common day 5 (CD163, CD206, CD25, Foxp3), and M1 or M2 macrophages and Treg cells were virtually absent day 10, while still present with full loading. The primary variable, CCR7/CD206 ratio day 5, was higher with full loading (p = 0.001) and the Treg cell fraction was lower (p < 0.001). Free cage activity loading is known to increase size and strength of the tendon in this model compared to Botox. Loading now appeared to delay the switch to an M2 type of inflammation with more Treg cells. It seems a prolonged M1 phase due to loading might make the tendon regenerate bigger. PMID:27405922

  17. RELATIONSHIP OF CAROTID ARTERIES INTIMA-MEDIA THICKNESS WITH INFECTIOUS, IMMUNE, METABOLIC FACTORS AND INFLAMMATION MARKERS IN HEALTHY PERSONS

    A. P. Shavrin

    2014-07-01

    Full Text Available Aim – to examine the relationship of arteries wall thickness with the indicators characterizing the infectious, immune, metabolic status inapparently healthy individuals.Materials and methods. The study included 342 patients (mean age 43.7 ± 0.5 years that in the process of cluster analysis on the thicknessof the intima-media thickness (IMT were divided into 3 groups. Group 1 consisted of patients with no risk factors of cardiovascular disease,2nd – patients with presence of these factors, 3rd – patients with atherosclerotic plaques in the carotid artery. All patients were examinedin complex: ultrasound of vessels measurement on the Aloka 5000 with IMT, evaluation of lipid profile, glucose level, determination of C-reactive protein (CRP in blood plasma and cytokines – tumor necrosis factor-α (TNF-α, interferon-γ (IFN-γ, interleukin (IL -1, -8, -4, specific antibody immunoglobulin G (IgG to cytomegalovirus (CMV, herpes simplex virus type 1 (HSV-1 , C. pneumoniae, H. pylori and β-hemolytic streptococci group A. Immune system status was assessed by innate and acquired immunity factors.Results. In groups of examined patients by increasing IMT of the common carotid artery infectious viruses (CMV, HSV-1 burden increased,what was obligatory for all groups. In the 3rd group, in 45 % of patients C. pneumoniae was found. In the 2nd and 3rd groups weakening ofacquired immunity was found out – reducing the total number of lymphocytes and T-lymphocytes, the increase of CRP and proinflammatory cytokines (IL-1, -8, IFN-γ, TNF-α, it was indicating development of inflammatory process, and in the third group it took characters of the system inflammatory response. In cluster analysis it was revealed that the process of thickening of the vascular wall is influenced by complex factors – infectious, metabolic and immune.Conclusion. The presence of the close relationship between the thickness of vessel walls and infectious, metabolic (lipid and

  18. RELATIONSHIP OF CAROTID ARTERIES INTIMA-MEDIA THICKNESS WITH INFECTIOUS, IMMUNE, METABOLIC FACTORS AND INFLAMMATION MARKERS IN HEALTHY PERSONS

    A. P. Shavrin

    2011-01-01

    Full Text Available Aim – to examine the relationship of arteries wall thickness with the indicators characterizing the infectious, immune, metabolic status inapparently healthy individuals.Materials and methods. The study included 342 patients (mean age 43.7 ± 0.5 years that in the process of cluster analysis on the thicknessof the intima-media thickness (IMT were divided into 3 groups. Group 1 consisted of patients with no risk factors of cardiovascular disease,2nd – patients with presence of these factors, 3rd – patients with atherosclerotic plaques in the carotid artery. All patients were examinedin complex: ultrasound of vessels measurement on the Aloka 5000 with IMT, evaluation of lipid profile, glucose level, determination of C-reactive protein (CRP in blood plasma and cytokines – tumor necrosis factor-α (TNF-α, interferon-γ (IFN-γ, interleukin (IL -1, -8, -4, specific antibody immunoglobulin G (IgG to cytomegalovirus (CMV, herpes simplex virus type 1 (HSV-1 , C. pneumoniae, H. pylori and β-hemolytic streptococci group A. Immune system status was assessed by innate and acquired immunity factors.Results. In groups of examined patients by increasing IMT of the common carotid artery infectious viruses (CMV, HSV-1 burden increased,what was obligatory for all groups. In the 3rd group, in 45 % of patients C. pneumoniae was found. In the 2nd and 3rd groups weakening ofacquired immunity was found out – reducing the total number of lymphocytes and T-lymphocytes, the increase of CRP and proinflammatory cytokines (IL-1, -8, IFN-γ, TNF-α, it was indicating development of inflammatory process, and in the third group it took characters of the system inflammatory response. In cluster analysis it was revealed that the process of thickening of the vascular wall is influenced by complex factors – infectious, metabolic and immune.Conclusion. The presence of the close relationship between the thickness of vessel walls and infectious, metabolic (lipid and

  19. Modified Self-adaptive Immune Genetic Algorithm for Optimization of Combustion Side Reaction of p-Xylene Oxidation

    陶莉莉; 孔祥东; 钟伟民; 钱锋

    2012-01-01

    In recent years, immune genetic algorithm (IGA) is gaining popularity for finding the optimal solution for non-linear optimization problems in many engineering applications. However, IGA with deterministic mutation factor suffers from the problem of premature convergence. In this study, a modified self-adaptive immune genetic algorithm (MSIGA) with two memory bases, in which immune concepts are applied to determine the mutation parameters, is proposed to improve the searching ability of the algorithm and maintain population diversity. Performance comparisons with other well-known population-based iterative algorithms show that the proposed method converges quickly to the global optimum and overcomes premature problem. This algorithm is applied to optimize a feed forward neural network to measure the content of products in the combustion side reaction of p-xylene oxidation, and satisfactory results are obtained.

  20. Safety of Probiotic Escherichia coli Strain Nissle 1917 Depends on Intestinal Microbiota and Adaptive Immunity of the Host▿

    Gronbach, Kerstin; Eberle, Ute; Müller, Martina; Ölschläger, Tobias A.; Dobrindt, Ulrich; Leithäuser, Frank; Niess, Jan Hendrik; Döring, Gerd; Reimann, Jörg; Autenrieth, Ingo B.; Frick, Julia-Stefanie

    2010-01-01

    Probiotics are viable microorganisms that are increasingly used for treatment of a variety of diseases. Occasionally, however, probiotics may have adverse clinical effects, including septicemia. Here we examined the role of the intestinal microbiota and the adaptive immune system in preventing translocation of probiotics (e.g., Escherichia coli Nissle). We challenged C57BL/6J mice raised under germfree conditions (GF-raised C57BL/6J mice) and Rag1−/− mice raised under germfree conditions (GF-...

  1. Cas9–crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria

    Gasiunas, Giedrius; Barrangou, Rodolphe; Horvath, Philippe; Siksnys, Virginijus

    2012-01-01

    Clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide adaptive immunity against viruses and plasmids in bacteria and archaea. The silencing of invading nucleic acids is executed by ribonucleoprotein complexes preloaded with small, interfering CRISPR RNAs (crRNAs) that act as guides for targeting and degradation of foreign nucleic acid. Here, we demonstrate that the Cas9–crRNA complex of the Streptococcus thermophilus CRISPR3/Cas system in...

  2. Adaptive Spam Detection Inspired by a Cross-Regulation Model of Immune Dynamics: A Study of Concept Drift

    Abi-Haidar, Alaa; Rocha, Luis M

    2008-01-01

    This paper proposes a novel solution to spam detection inspired by a model of the adaptive immune system known as the crossregulation model. We report on the testing of a preliminary algorithm on six e-mail corpora. We also compare our results statically and dynamically with those obtained by the Naive Bayes classifier and another binary classification method we developed previously for biomedical text-mining applications. We show that the cross-regulation model is competitive against those a...

  3. Temporomandibular joint inflammation activates glial and immune cells in both the trigeminal ganglia and in the spinal trigeminal nucleus

    Jasmin Luc

    2010-12-01

    Full Text Available Abstract Background Glial cells have been shown to directly participate to the genesis and maintenance of chronic pain in both the sensory ganglia and the central nervous system (CNS. Indeed, glial cell activation has been reported in both the dorsal root ganglia and the spinal cord following injury or inflammation of the sciatic nerve, but no data are currently available in animal models of trigeminal sensitization. Therefore, in the present study, we evaluated glial cell activation in the trigeminal-spinal system following injection of the Complete Freund's Adjuvant (CFA into the temporomandibular joint, which generates inflammatory pain and trigeminal hypersensitivity. Results CFA-injected animals showed ipsilateral mechanical allodynia and temporomandibular joint edema, accompanied in the trigeminal ganglion by a strong increase in the number of GFAP-positive satellite glial cells encircling neurons and by the activation of resident macrophages. Seventy-two hours after CFA injection, activated microglial cells were observed in the ipsilateral trigeminal subnucleus caudalis and in the cervical dorsal horn, with a significant up-regulation of Iba1 immunoreactivity, but no signs of reactive astrogliosis were detected in the same areas. Since the purinergic system has been implicated in the activation of microglial cells during neuropathic pain, we have also evaluated the expression of the microglial-specific P2Y12 receptor subtype. No upregulation of this receptor was detected following induction of TMJ inflammation, suggesting that any possible role of P2Y12 in this paradigm of inflammatory pain does not involve changes in receptor expression. Conclusions Our data indicate that specific glial cell populations become activated in both the trigeminal ganglia and the CNS following induction of temporomandibular joint inflammation, and suggest that they might represent innovative targets for controlling pain during trigeminal nerve sensitization.

  4. A peptide derived from the parasite receptor, complement C2 receptor inhibitor trispanning, suppresses immune complex-mediated inflammation in mice.

    Inal, Jameel M; Schneider, Brigitte; Armanini, Marta; Schifferli, Jürg A

    2003-04-15

    Complement C2 receptor inhibitor trispanning (CRIT) is a Schistosoma protein that binds the human complement protein, C2. We recently showed that peptides based on the ligand binding region of CRIT inhibit the classical pathway (CP) of complement activation in human serum, using hemolytic assays and so speculated that on the parasite surface CRIT has the function of evading human complement. We now show that in vitro the C2-binding 11-aa C terminus of the first extracellular domain of CRIT, a 1.3-kDa peptide termed CRIT-H17, inhibits CP activation in a species-specific manner, inhibiting mouse and rat complement but not that from guinea pig. Hitherto, the ability of CRIT to regulate complement in vivo has not been assessed. In this study we show that by inhibiting the CP, CRIT-H17 is able to reduce immune complex-mediated inflammation (dermal reversed passive Arthus reaction) in BALB/c mice. Upon intradermal injection of CRIT-H17, and similarly with recombinant soluble complement receptor type 1, there was a 41% reduction in edema and hemorrhage, a 72% reduction in neutrophil influx, and a reduced C3 deposition. Furthermore, when H17 was administered i.v. at a 1 mg/kg dose, inflammation was reduced by 31%. We propose that CRIT-H17 is a potential therapeutic agent against CP complement-mediated inflammatory tissue destruction. PMID:12682267

  5. Mouse models of intestinal inflammation and cancer.

    Westbrook, Aya M; Szakmary, Akos; Schiestl, Robert H

    2016-09-01

    Chronic inflammation is strongly associated with approximately one-fifth of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here, we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With

  6. Alcohol and Inflammation & Immune Responses: Summary of the 2006 Alcohol and Immunology Research Interest Group (AIRIG) meeting

    Waldschmidt, Thomas J.; Cook, Robert T.; Kovacs, Elizabeth J.

    2008-01-01

    The 11th annual meeting of the Alcohol and Immunology Research Interest Group (AIRIG) was held at Loyola University Medical Center, Maywood, Illinois on November 17, 2006. The AIRIG meeting is held annually to exchange new findings and ideas that arise from onging research examining the effects of alcohol intake on the immune system. The event consisted of five sessions, two of which featured plenary talks from invited speakers, two with oral presentations from selected abstracts, and a final...

  7. Endogenous Control of Immunity against Infection: Tenascin-C Regulates TLR4-Mediated Inflammation via MicroRNA-155

    2012-01-01

    Summary Endogenous molecules generated upon pathogen invasion or tissue damage serve as danger signals that activate host defense; however, their precise immunological role remains unclear. Tenascin-C is an extracellular matrix glycoprotein that is specifically induced upon injury and infection. Here, we show that its expression is required to generate an effective immune response to bacterial lipopolysaccharide (LPS) during experimental sepsis in vivo. Tenascin-C enables macrophage translati...

  8. Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling

    Kang, Young Jun; Bang, Bo-Ram; Han, Kyung Ho; Hong, Lixin; Shim, Eun-Jin; Ma, Jianhui; Lerner, Richard A.; Otsuka, Motoyuki

    2015-01-01

    The receptor-interacting protein kinase 3 (RIPK3) plays crucial roles in programmed necrosis and innate inflammatory responses. However, a little is known about the involvement of RIPK3 in NKT cell-mediated immune responses. Here, we demonstrate that RIPK3 plays an essential role in NKT cell function via activation of the mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5). RIPK3-mediated activation of PGAM5 promotes the expression of cytokines by facilitating nuclear translocation of...

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

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

    2012-01-01

    Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by Candida albicans. Despite its prevalence, little is known about C. albicans-specific immunity in the oral mucosa. Vaccines against Candida generate both Th1 and Th17 responses, and considerable evidence implicates IL-17 in immunity to OPC. However, IL-17 is also produced by innate immune cells that are remarkably similar to Th17 cells, expressing the same markers and localizing to similar mucosal sites. To date, the relat...

  10. Activation of an immune-regulatory macrophage response and inhibition of lung inflammation in a mouse model of COPD using heat-shock protein alpha B-crystallin-loaded PLGA microparticles

    van Noort, Johannes M.; Bsibsi, Malika; Nacken, Peter J.; Gerritsen, Wouter H.; Amor, Sandra; Holtman, Inge R.; Boddeke, Erik; van Ark, Ingrid; Leusink-Muis, Thea; Folkerts, Gert; Hennink, Wim E.; Amidi, Maryam

    2013-01-01

    As an extracellular protein, the small heat-shock protein alpha B-crystallin (HSPB5) has anti-inflammatory effects in several mouse models of inflammation. Here, we show that these effects are associated with the ability of HSPB5 to activate an immune-regulatory response in macrophages via endosomal

  11. Immunity

    2008-01-01

    2008254 Prokaryotic expression and immunogenicity of Fba,a novel fibronectin-binding protein of group A streptococcus.MA Cuiqing(马翠柳),et al.Dept Immunol,Basic Med Coll,Hebei Med Univ,Shijiazhuang 050017.Chin J Infect Dis 2008;26(3):146-150.Objective To express the novel fibronectin-binding protein Fba ofgroupAstreptococcus(GAS)and analyze its immunogenicity,so to evaluate the immune responses to GAS infection.Methods fbagene was amplified by

  12. Disruptions of Host Immunity and Inflammation by Giardia Duodenalis: Potential Consequences for Co-Infections in the Gastro-Intestinal Tract

    James A. Cotton

    2015-11-01

    Full Text Available Giardia duodenalis (syn. G. intestinalis, or G. lamblia is a leading cause of waterborne diarrheal disease that infects hundreds of millions of people annually. Research on Giardia has greatly expanded within the last few years, and our understanding of the pathophysiology and immunology on this parasite is ever increasing. At peak infection, Giardia trophozoites induce pathophysiological responses that culminate in the development of diarrheal disease. However, human data has suggested that the intestinal mucosa of Giardia-infected individuals is devoid of signs of overt intestinal inflammation, an observation that is reproduced in animal models. Thus, our understanding of host inflammatory responses to the parasite remain incompletely understood and human studies and experimental data have produced conflicting results. It is now also apparent that certain Giardia infections contain mechanisms capable of modulating their host’s immune responses. As the oral route of Giardia infection is shared with many other gastrointestinal (GI pathogens, co-infections may often occur, especially in places with poor sanitation and/or improper treatment of drinking water. Moreover, Giardia infections may modulate host immune responses and have been found to protect against the development of diarrheal disease in developing countries. The following review summarizes our current understanding of the immunomodulatory mechanisms of Giardia infections and their consequences for the host, and highlights areas for future research. Potential implications of these immunomodulatory effects during GI co-infection are also discussed.

  13. CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation.

    Paramel, Geena Varghese; Folkersen, Lasse; Strawbridge, Rona J; Elmabsout, Ali Ateia; Särndahl, Eva; Lundman, Pia; Jansson, Jan-Håkan; Hansson, Göran K; Sirsjö, Allan; Fransén, Karin

    2013-10-01

    Inflammation is a key factor in the development of atherosclerotic coronary artery disease. It is promoted through the inflammasome, a molecular machine that produces IL (interleukin)-1β in response to cholesterol crystal accumulation in macrophages. The CARD8 (caspase recruitment domain 8) protein modulates this process by suppressing caspase 1 and the transcription factor NF-κB (nuclear factor κB). The expression of CARD8 mRNA was examined in atherosclerotic vascular tissue and the impact on MI (myocardial infarction) of a polymorphism in the CARD8 gene determined. CARD8 mRNA was analysed by microarray of human atherosclerotic tissue and compared with transplant donor arterial tissue. Microarray analysis was performed for proximal genes associated with the rs2043211 locus in plaque. The CARD8 rs2043211 polymorphism was analysed by genotyping of two Swedish MI cohorts, FIA (First Myocardial Infarction in Northern Sweden) and SCARF (Stockholm Coronary Atherosclerosis Risk Factor). The CRP (C-reactive protein) level was measured in both cohorts, but the levels of the pro-inflammatory cytokines IL-1β, IL-18, TNF (tumour necrosis factor) and MCP-1 (monocyte chemoattractant protein) were measured in sera available from the SCARF cohort. CARD8 mRNA was highly expressed in atherosclerotic plaques compared with the expression in transplant donor vessel (P<0.00001). The minor allele was associated with lower expression of CARD8 in the plaques, suggesting that CARD8 may promote inflammation. Carriers of the minor allele of the rs2043211 polymorphism also displayed lower circulating CRP and lower levels of the pro-atherosclerotic chemokine MCP-1. However, no significant association could be detected between this polymorphism and MI in the two cohorts. Genetic alterations in the CARD8 gene therefore seem to be of limited importance for the development of MI. PMID:23611467

  14. Cellular adaptive immune response against porcine circovirus type 2 in subclinically infected pigs

    Gerber Heidi

    2009-12-01

    Full Text Available Abstract Background Porcine circovirus type 2 (PCV2 is a dominant causative agent of postweaning multisystemic wasting syndrome (PMWS, a multifactorial disease complex with putative immunosuppressive characteristics. Little is known about adaptive PCV2-specific immune responses in infected pigs. Therefore, the T and B cell responses following PCV2 infection in 3-week old SPF piglets infected with PCV2 or PCV2 plus porcine parvovirus (PPV were studied. Results All animals were asymptomatically infected. At 7 days post infection (d p.i., B lymphocyte and T lymphocyte numbers decreased in the dual infected, but not in the single infected piglets. At this time point a transient PCV2 viraemia was noted in the PCV2 infected groups. Antibodies against the infecting virus were detectable at day 24-28 p.i. for anti-PCV2 antibodies and at day 10 p.i. for anti-PPV antibodies, with no apparent influence of PCV2 on the early PPV antibody development. In the animals infected with PPV alone, IFN-γ secreting cells (SC that were not specific for PCV2 were detected by ELISPOT assay at day 7 p.i. Interestingly, this response was absent in the PCV2/PPV dual infected animals. PCV2-specific IFN-γ SC were observed in the PCV2/PPV infected group at 7 d p.i. and in the PCV2 single infected group at 21 d p.i. A reduction in the numbers of IFN-γ SC was observed following anti-CD4 and anti-CD8 antibody treatment, suggesting roles for both CD4+ and CD8+ T cells in the response against PCV2 infection. This was supported by an observed increase in the percentage of IFN-γ positive CD8hi cytotoxic T cells as well as IFN-γ positive CD8-/low helper T cells after PCV2 in vitro re-stimulation. Conclusions Infection of weaned SPF piglets with PCV2 alone or combined with PPV does not induce disease and in both cases a relatively slow anti-PCV2 antibody response and weak T lymphocyte responses were found. Knowledge on such immunological characteristics is important for both PCV2

  15. Trappin-2/Elafin Modulate Innate Immune Responses of Human Endometrial Epithelial Cells to PolyI∶C

    Drannik, Anna G.; Kakon Nag; Xiao-Dan Yao; Henrick, Bethany M.; Jean-Michel Sallenave; Rosenthal, Kenneth L

    2012-01-01

    BACKGROUND: Upon viral recognition, innate and adaptive antiviral immune responses are initiated by genital epithelial cells (ECs) to eradicate or contain viral infection. Such responses, however, are often accompanied by inflammation that contributes to acquisition and progression of sexually transmitted infections (STIs). Hence, interventions/factors enhancing antiviral protection while reducing inflammation may prove beneficial in controlling the spread of STIs. Serine antiprotease trappin...

  16. A Comparison of the Adaptive Immune Response between Recovered Anthrax Patients and Individuals Receiving Three Different Anthrax Vaccines.

    Laws, Thomas R; Kuchuloria, Tinatin; Chitadze, Nazibriola; Little, Stephen F; Webster, Wendy M; Debes, Amanda K; Saginadze, Salome; Tsertsvadze, Nikoloz; Chubinidze, Mariam; Rivard, Robert G; Tsanava, Shota; Dyson, Edward H; Simpson, Andrew J H; Hepburn, Matthew J; Trapaidze, Nino

    2016-01-01

    Several different human vaccines are available to protect against anthrax. We compared the human adaptive immune responses generated by three different anthrax vaccines or by previous exposure to cutaneous anthrax. Adaptive immunity was measured by ELISPOT to count cells that produce interferon (IFN)-γ in response to restimulation ex vivo with the anthrax toxin components PA, LF and EF and by measuring circulating IgG specific to these antigens. Neutralising activity of antisera against anthrax toxin was also assayed. We found that the different exposures to anthrax antigens promoted varying immune responses. Cutaneous anthrax promoted strong IFN-γ responses to all three antigens and antibody responses to PA and LF. The American AVA and Russian LAAV vaccines induced antibody responses to PA only. The British AVP vaccine produced IFN-γ responses to EF and antibody responses to all three antigens. Anti-PA (in AVA and LAAV vaccinees) or anti-LF (in AVP vaccinees) antibody titres correlated with toxin neutralisation activities. Our study is the first to compare all three vaccines in humans and show the diversity of responses against anthrax antigens. PMID:27007118

  17. A Comparison of the Adaptive Immune Response between Recovered Anthrax Patients and Individuals Receiving Three Different Anthrax Vaccines.

    Thomas R Laws

    Full Text Available Several different human vaccines are available to protect against anthrax. We compared the human adaptive immune responses generated by three different anthrax vaccines or by previous exposure to cutaneous anthrax. Adaptive immunity was measured by ELISPOT to count cells that produce interferon (IFN-γ in response to restimulation ex vivo with the anthrax toxin components PA, LF and EF and by measuring circulating IgG specific to these antigens. Neutralising activity of antisera against anthrax toxin was also assayed. We found that the different exposures to anthrax antigens promoted varying immune responses. Cutaneous anthrax promoted strong IFN-γ responses to all three antigens and antibody responses to PA and LF. The American AVA and Russian LAAV vaccines induced antibody responses to PA only. The British AVP vaccine produced IFN-γ responses to EF and antibody responses to all three antigens. Anti-PA (in AVA and LAAV vaccinees or anti-LF (in AVP vaccinees antibody titres correlated with toxin neutralisation activities. Our study is the first to compare all three vaccines in humans and show the diversity of responses against anthrax antigens.

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

    Corcos, D

    2015-11-01

    Adaptive immunity is a complex system that appeared twice in vertebrates (in gnathostomes and in jawless fish) although it is not required for invertebrate defence. The adaptive immune system is tightly associated with self-non-self discrimination, and it is now clear that this interplay is not limited to the prevention of autoreactivity. Micro-organisms are usually considered for their pathogenicity or symbiotic ability, but, for most small metazoans, they mainly constitute food. Vertebrates are characterized by feeding by predation on larger preys, when compared to their ancestors who were filter feeders and ate micro-organisms. Predation gives a strong selective advantage, not only due to the availability of new food resources but also by the ability to eliminate competitors for environmental resources (intraguild predation (IGP)). Unlike size-structured IGP, intraspecific predation of juveniles, zygotes or gametes can be detrimental for species fitness in some circumstances. The ability of individuals to recognize highly polymorphic molecules on the surface of gametes present in the plankton and so distinguish self versus non-self gametes might have constituted a strong selective advantage in intraspecific competition. Here, I propose the theory that the capacity to rearrange receptors has been selected in ancestral vertebrates as a consequence of this strong need for discriminating between hetero-cannibalism versus filial cannibalism. This evolutionary origin sheds light on presently unexplained features of the immune system, including the existence of regulatory T cells and of non-pathogenic natural autoimmunity. PMID:26286030

  19. A Comparison of the Adaptive Immune Response between Recovered Anthrax Patients and Individuals Receiving Three Different Anthrax Vaccines

    Laws, Thomas R.; Kuchuloria, Tinatin; Chitadze, Nazibriola; Little, Stephen F.; Webster, Wendy M.; Debes, Amanda K.; Saginadze, Salome; Tsertsvadze, Nikoloz; Chubinidze, Mariam; Rivard, Robert G.; Tsanava, Shota; Dyson, Edward H.; Simpson, Andrew J. H.; Hepburn, Matthew J.; Trapaidze, Nino

    2016-01-01

    Several different human vaccines are available to protect against anthrax. We compared the human adaptive immune responses generated by three different anthrax vaccines or by previous exposure to cutaneous anthrax. Adaptive immunity was measured by ELISPOT to count cells that produce interferon (IFN)-γ in response to restimulation ex vivo with the anthrax toxin components PA, LF and EF and by measuring circulating IgG specific to these antigens. Neutralising activity of antisera against anthrax toxin was also assayed. We found that the different exposures to anthrax antigens promoted varying immune responses. Cutaneous anthrax promoted strong IFN-γ responses to all three antigens and antibody responses to PA and LF. The American AVA and Russian LAAV vaccines induced antibody responses to PA only. The British AVP vaccine produced IFN-γ responses to EF and antibody responses to all three antigens. Anti-PA (in AVA and LAAV vaccinees) or anti-LF (in AVP vaccinees) antibody titres correlated with toxin neutralisation activities. Our study is the first to compare all three vaccines in humans and show the diversity of responses against anthrax antigens. PMID:27007118

  20. Systemic Inflammation and the Brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration.

    Roman eSankowski; Simone eMader; Sergio Iván Valdés-Ferrer

    2015-01-01

    The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The central nervous system (CNS) feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. Cytokines, chemokines, damage-associated soluble m...

  1. Systemic Inflammation and the Brain: Novel Roles of Genetic, Molecular, and Environmental Cues as Drivers of Neurodegeneration

    Sankowski, Roman; Mader, Simone; Valdés-Ferrer, Sergio Iván

    2015-01-01

    The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system (CNS) coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The CNS feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. Cytokines, chemokines, and damage-associated soluble mediators of sys...

  2. Beyond corticosteroids: future prospects in the management of inflammation in COPD

    Roche, N; Marthan, R.; P. Berger; A. Chambellan; Chanez, P; Aguilaniu, B; P-Y Brillet; P-R. Burgel; Chaouat, A.; Devillier, P; Escamilla, R.; Louis, R; H. Mal; J-F Muir; Pérez, T

    2011-01-01

    Inflammation plays a central role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Exposure to cigarette smoke induces the recruitment of inflammatory cells in the airways and stimulates innate and adaptive immune mechanisms. Airway inflammation is involved in increased bronchial wall thickness, increased bronchial smooth muscle tone, mucus hypersecretion and loss of parenchymal elastic structures. Oxidative stress impairs tissue integrity, accelerates lung ageing and r...

  3. Heat-shock proteins in infection-mediated inflammation-induced tumorigenesis

    Li Zihai; Goldstein Mark G

    2009-01-01

    Abstract Inflammation is a necessary albeit insufficient component of tumorigenesis in some cancers. Infectious agents directly implicated in tumorigenesis have been shown to induce inflammation. This process involves both the innate and adaptive components of the immune system which contribute to tumor angiogenesis, tumor tolerance and metastatic properties of neoplasms. Recently, heat-shock proteins have been identified as mediators of this inflammatory process and thus may provide a link b...

  4. Osteopontin Expression in Acute Immune Response Mediates Hippocampal Synaptogenesis and Adaptive Outcome Following Cortical Brain Injury

    Chan, Julie L.; Reeves, Thomas M.; Phillips, Linda L.

    2014-01-01

    Traumatic brain injury (TBI) produces axotomy, deafferentation and reactive synaptogenesis. Inflammation influences synaptic repair, and the novel brain cytokine osteopontin (OPN) has potential to support axon regeneration through exposure of its integrin receptor binding sites. This study explored whether OPN secretion and proteolysis by matrix metalloproteinases (MMPs) mediate the initial degenerative phase of synaptogenesis, targeting reactive neuroglia to affect successful repair. Adult r...

  5. Endogenous Control of Immunity against Infection: Tenascin-C Regulates TLR4-Mediated Inflammation via MicroRNA-155

    Anna M. Piccinini

    2012-10-01

    Full Text Available Endogenous molecules generated upon pathogen invasion or tissue damage serve as danger signals that activate host defense; however, their precise immunological role remains unclear. Tenascin-C is an extracellular matrix glycoprotein that is specifically induced upon injury and infection. Here, we show that its expression is required to generate an effective immune response to bacterial lipopolysaccharide (LPS during experimental sepsis in vivo. Tenascin-C enables macrophage translation of proinflammatory cytokines upon LPS activation of toll-like receptor 4 (TLR4 and suppresses the synthesis of anti-inflammatory cytokines. It mediates posttranscriptional control of a specific subset of inflammatory mediators via induction of the microRNA miR-155. Thus, tenascin-C plays a key role in regulating the inflammatory axis during pathogenic activation of TLR signaling.

  6. Endogenous control of immunity against infection: tenascin-C regulates TLR4-mediated inflammation via microRNA-155.

    Piccinini, Anna M; Midwood, Kim S

    2012-10-25

    Endogenous molecules generated upon pathogen invasion or tissue damage serve as danger signals that activate host defense; however, their precise immunological role remains unclear. Tenascin-C is an extracellular matrix glycoprotein that is specifically induced upon injury and infection. Here, we show that its expression is required to generate an effective immune response to bacterial lipopolysaccharide (LPS) during experimental sepsis in vivo. Tenascin-C enables macrophage translation of proinflammatory cytokines upon LPS activation of toll-like receptor 4 (TLR4) and suppresses the synthesis of anti-inflammatory cytokines. It mediates posttranscriptional control of a specific subset of inflammatory mediators via induction of the microRNA miR-155. Thus, tenascin-C plays a key role in regulating the inflammatory axis during pathogenic activation of TLR signaling. PMID:23084751

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

    Gjini, Erida; Brito, Patricia H.

    2016-01-01

    Antimicrobial resistance of infectious agents is a growing problem worldwide. To prevent the continuing selection and spread of drug resistance, rational design of antibiotic treatment is needed, and the question of aggressive vs. moderate therapies is currently heatedly debated. Host immunity is an important, but often-overlooked factor in the clearance of drug-resistant infections. In this work, we compare aggressive and moderate antibiotic treatment, accounting for host immunity effects. W...

  8. Leptospira and Inflammation

    C. F. Gonçalves-de-Albuquerque

    2012-01-01

    Full Text Available Leptospirosis is an important zoonosis and has a worldwide impact on public health. This paper will discuss both the role of immunogenic and pathogenic molecules during leptospirosis infection and possible new targets for immunotherapy against leptospira components. Leptospira, possess a wide variety of mechanisms that allow them to evade the host immune system and cause infection. Many molecules contribute to the ability of Leptospira to adhere, invade, and colonize. The recent sequencing of the Leptospira genome has increased our knowledge about this pathogen. Although the virulence factors, molecular targets, mechanisms of inflammation, and signaling pathways triggered by leptospiral antigens have been studied, some questions are still unanswered. Toll-like receptors (TLRs are the primary sensors of invading pathogens. TLRs recognize conserved microbial pattern molecules and activate signaling pathways that are pivotal to innate and adaptive immune responses. Recently, a new molecular target has emerged—the Na/K-ATPase—which may contribute to inflammatory and metabolic alteration in this syndrome. Na/K-ATPase is a target for specific fatty acids of host origin and for bacterial components such as the glycolipoprotein fraction (GLP that may lead to inflammasome activation. We propose that in addition to TLRs, Na/K-ATPase may play a role in the innate response to leptospirosis infection.

  9. The adaptor CARD9 is required for adaptive but not innate immunity to oral mucosal Candida albicans infections.

    Bishu, Shrinivas; Hernández-Santos, Nydiaris; Simpson-Abelson, Michelle R; Huppler, Anna R; Conti, Heather R; Ghilardi, Nico; Mamo, Anna J; Gaffen, Sarah L

    2014-03-01

    Oropharyngeal candidiasis (OPC [thrush]) is an opportunistic infection caused by the commensal fungus Candida albicans. OPC is common in individuals with HIV/AIDS, infants, patients on chemotherapy, and individuals with congenital immune defects. Immunity to OPC is strongly dependent on the interleukin-23 (IL-23)/IL-17R axis, as mice and humans with defects in IL-17R signaling (IL17F, ACT1, IL-17RA) or in genes that direct Th17 differentiation (STAT3, STAT1, CARD9) are prone to mucocutaneous candidiasis. Conventional Th17 cells are induced in response to C. albicans infection via signals from C-type lectin receptors, which signal through the adaptor CARD9, leading to production of Th17-inducing cytokines such as IL-6, IL-1β, and IL-23. Recent data indicate that IL-17 can also be made by numerous innate cell subsets. These innate "type 17" cells resemble conventional Th17 cells, but they can be activated without need for prior antigen exposure. Because C. albicans is not a commensal organism in rodents and mice are thus naive to this fungus, we had the opportunity to assess the role of CARD9 in innate versus adaptive responses using an OPC infection model. As expected, CARD9(-/-) mice failed to mount an adaptive Th17 response following oral Candida infection. Surprisingly, however, CARD9(-/-) mice had preserved innate IL-17-dependent responses to Candida and were almost fully resistant to OPC. Thus, CARD9 is important primarily for adaptive immunity to C. albicans, whereas alternate recognition systems appear to be needed for effective innate responses. PMID:24379290

  10. Adaptive Spam Detection Inspired by a Cross-Regulation Model of Immune Dynamics: A Study of Concept Drift

    Abi-Haidar, Alaa; 10.1007/978-3-540-85072-4_4

    2008-01-01

    This paper proposes a novel solution to spam detection inspired by a model of the adaptive immune system known as the crossregulation model. We report on the testing of a preliminary algorithm on six e-mail corpora. We also compare our results statically and dynamically with those obtained by the Naive Bayes classifier and another binary classification method we developed previously for biomedical text-mining applications. We show that the cross-regulation model is competitive against those and thus promising as a bio-inspired algorithm for spam detection in particular, and binary classification in general.

  11. Adaptive immune defects against glycoantigens in chronic granulomatous disease via dysregulated nitric oxide production

    Lewis, Colleen J.; Cobb, Brian A

    2011-01-01

    Chronic granulomatous disease (CGD) is a primary immunodeficiency defined by mutations in the NADPH oxidase complex leading to reduced superoxide production, increased susceptibility to infection, chronic inflammation, and recurring abscess and granuloma formation. Here, we found that CGD mice were hyperresponsive to abscess-inducing T-cell-dependent carbohydrate antigens (glycoantigens) due to a ten-fold increase in NO production within APCs, which is known to be necessary for glycoantigen p...

  12. Control of Dichotomic Innate and Adaptive Immune Responses by Artery Tertiary Lymphoid Organs in Atherosclerosis

    Falk eWeih; Rolf eGräbner; Desheng eHu; Michael eBeer; Andreas Johann Habenicht

    2012-01-01

    Tertiary lymphoid organs (TLOs) emerge in tissues in response to nonresolving inflammation such as chronic infection, graft rejection, and autoimmune disease. We identified artery TLOs (ATLOs) in the adventitia adjacent to atherosclerotic plaques of aged hyperlipidemic ApoE-/- mice. ATLOs are structured into T cell areas harboring conventional dendritic cells (cDCs) and monocyte-derived DCs (mDCs); B cell follicles containing follicular dendritic cells (FDCs) within activated germinal centers...

  13. The many paths to asthma: phenotype shaped by innate and adaptive immunity

    Kim, Hye Young; DeKruyff, Rosemarie H.; Umetsu, Dale T.

    2010-01-01

    Asthma is a very complex and heterogeneous disease that is characterized by airway inflammation and airway hyper-reactivity (AHR). The pathogenesis of asthma is associated with environmental factors, many cell types, and several molecular and cellular pathways. These include allergic, non-allergic and intrinsic pathways, which involve many cell types and cytokines. Animal models of asthma have helped to clarify some of the underlying mechanisms of asthma, demonstrating the importance of T hel...

  14. Standardized extract of Tinospora crispa stimulates innate and adaptive immune responses in Balb/c mice.

    Ahmad, Waqas; Jantan, Ibrahim; Kumolosasi, Endang; Bukhari, Syed Nasir Abbas

    2016-03-01

    Standardized extract of Tinospora crispa has been shown to exhibit immunostimulatory effects on innate immune responses in Wistar-Kyoto rats by enhancing neutrophil and T cell-mediated immunity. In this study the immunostimulatory effects of T. crispa were further investigated on the cellular immune response by determining its effect on nitric oxide (NO) production ability, peritoneal macrophage phagocytosis and delayed type hypersensitivity (DTH), whereas the humoral immune response was evaluated through the measurement of serum immunoglobulins (IgG and IgM) and serum lysozyme levels. Male Balb/c mice were immunized with 200 μL of 5 × 10(9) sheep red blood cells (sRBCs) per mL on day 0 and orally administered with 50, 100 and 200 mg per kg of ethanol extract of T. crispa for 14 days. Syringin and magnoflorine were qualitatively and quantitatively analyzed in the extract as chemical markers by using a validated reversed-phase high performance liquid chromatography method. T. crispa extract (TCE) considerably improved the peritoneal macrophages' ability to engulf FITC-labeled E. coli in a dose-dependent manner. TCE also dose-dependently promoted NO production in peritoneal macrophages activated by a lipopolysaccharide (LPS) and markedly potentiated the sRBS-induced swelling rate of the mice paw in DTH. The extract significantly enhanced the level of serum immunoglobulins, showing maximum activity at 100 mg kg(-1). Compared to the control groups, the serum lysozyme level and myeloperoxidase (MPO) activity were significantly higher in extract-treated groups. These findings suggest that T. crispa possesses strong immunostimulatory activities and might act as a natural immunomodulator as well as a potential nutraceutical for the modulation of the immune response. PMID:26839149

  15. Nitric Oxide-Releasing Nanoparticles Prevent Propionibacterium acnes-Induced Inflammation by Both Clearing the Organism and Inhibiting Microbial Stimulation of the Innate Immune Response.

    Qin, Min; Landriscina, Angelo; Rosen, Jamie M; Wei, Gabrielle; Kao, Stephanie; Olcott, William; Agak, George W; Paz, Karin B; Bonventre, Josephine; Clendaniel, Alicea; Harper, Stacey; Adler, Brandon L; Krausz, Aimee E; Friedman, Joel M; Nosanchuk, Joshua D; Kim, Jenny; Friedman, Adam J

    2015-11-01

    Propionibacterium acnes induction of IL-1 cytokines through the NLRP3 (NLR, nucleotide oligomerization domain-like receptor) inflammasome was recently highlighted as a dominant etiological factor for acne vulgaris. Therefore, therapeutics targeting both the stimulus and the cascade would be ideal. Nitric oxide (NO), a potent biological messenger, has documented broad-spectrum antimicrobial and immunomodulatory properties. To harness these characteristics to target acne, we used an established nanotechnology capable of generating/releasing NO over time (NO-np). P. acnes was found to be highly sensitive to all concentrations of NO-np tested, although human keratinocyte, monocyte, and embryonic zebra fish assays revealed no cytotoxicity. NO-np significantly suppressed IL-1β, tumor necrosis factor-α (TNF-α), IL-8, and IL-6 from human monocytes, and IL-8 and IL-6 from human keratinocytes, respectively. Importantly, silencing of NLRP3 expression by small interfering RNA did not limit NO-np inhibition of IL-1 β secretion from monocytes, and neither TNF-α nor IL-6 secretion, nor inhibition by NO-np was found to be dependent on this pathway. The observed mechanism by which NO-np impacts IL-1β secretion was through inhibition of caspase-1 and IL-1β gene expression. Together, these data suggest that NO-np can effectively prevent P. acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response. PMID:26172313

  16. Expression of Protease-Activated Receptor-2 in SZ95 Sebocytes and its Role in Sebaceous Lipogenesis, Inflammation, and Innate Immunity.

    Lee, Sang E; Kim, Ji-Min; Jeong, Se K; Choi, Eung H; Zouboulis, Christos C; Lee, Seung H

    2015-09-01

    Protease-activated receptor-2 (PAR-2) functions as innate biosensor for proteases and regulates numerous functions of the skin. However, the expression and physiological role of PAR-2 in sebocytes remain to be elucidated. Here, we identified PAR-2 expression in SZ95 sebocytes at both mRNA and protein levels. Intracellular Ca(2+) mobilization by PAR-2 agonist peptide (PAR-2 AP) or Propionibacterium acnes (P. acnes) culture supernatant was detected, indicating that P. acnes is a potent activator of PAR-2 on sebocytes. The small interfering RNA (siRNA)-mediated PAR-2 knockdown in sebocytes resulted in defective differentiation and lipogenesis. PAR-2 AP treatment enhanced lipogenesis and sterol response element-binding protein-1 (SREBP-1) expression, suggesting a role of PAR-2 in the differentiation and lipogenesis of sebocytes. Moreover, PAR-2 AP induced cytokines and human β-defensin-2 (hBD-2) transcription in sebocytes. PAR-2 expression was increased in sebaceous glands of acne lesions. PAR-2 silencing by siRNA abrogated the increase in sebaceous lipogenesis and SREBP-1 expression by P. acnes supernatant. PAR-2 knockdown also inhibited the P. acnes supernatant-induced expression of cytokines and hBD-2. In conclusion, PAR-2 is expressed in SZ95 sebocytes and mediates differentiation, lipogenesis, inflammation, and innate immunity in response to P. acnes. Therefore, PAR-2 might be a therapeutic target for sebaceous gland disorders such as acne. PMID:25880702

  17. Thymus involvement in immune system adaptive response to fractionated low-level γ-radiation

    In experiments with normal and thymoctomized rats it has been revealed that exposure of normal animals to 0.35 Gy of γ-radiation induces changes in blood cells subsets, depression of NK functional activity, decrease in polymorphonuclear leukocyte basal chemiluminescence level, supression of the delayed type of hypersensitivity reaction and stimulation of local IgE-synthesis in respiratory organs. At the same time irradiation of adult thymectomized animals did not resulted in significant fluctuations in cellular and humoral immunity indices as well as blood cells functional activity level. Some mechanisms of radiation-induced immune system disturbances mediate via thymus are discussed

  18. Electro-Acupuncture at Acupoint ST36 Reduces Inflammation and Regulates Immune Activity in Collagen-Induced Arthritic Mice

    Yun-Kyoung Yim

    2007-01-01

    Full Text Available This study aimed to investigate the anti-inflammatory, anti-arthritic and immuno-regulatory effects of electro-acupuncture (EA at ST36 on Collagen-induced arthritis (CIA in mice. Male DBA/1J mice were divided into five groups: Normal, Control, NR (needle retention, EAI and EAII. All mice except those in the normal group were immunized with Collagen II for arthritis induction. Acupuncture needles were inserted into mice ST36 and electrical currents at a frequency of 2 Hz in a continuous rectangular wave form were conducted through the needles for 15 min, 3 times a week. EA treatments were administered for 5 weeks in the EAI group and for 9 weeks in the EAII group. The mice in the NR group were acupunctured in the same manner as the EA groups and the needles were retained for 15 min without electrical stimulation. CIA incidence analysis, ELISA, histological analysis and FACS analysis were performed to evaluate the effect of EA on CIA. EA at ST36 significantly reduced CIA incidence, IL-6, TNF-a, INF-γ, collagen II antibody, IgG and IgM levels in CIA mice serum and prevented knee joint destruction. EA at ST36 also reduced CD69+/CD3e+ cells and CD11a+/CD19+ cells in CIA mice lymph nodes, and CD11b+/Gr1+ cells in CIA mice knee joints. The ratios of CD3e+ cells to CD19+ cells, and CD8+ cells to CD4+ cells were maintained closer to the normal range in the EA groups as compared with the control group or the NR group. EAII was more effective than EAI throughout all the measurements. The NR was effective as well, though less effective than EA. EA at ST36 may have an anti-inflammatory, anti-arthritic and immuno-regulatory effects on CIA in mice. The effectiveness is stronger when EA starts earlier and is applied longer. Needle retention without electrical stimulation may be effective on CIA as well, however less effective than EA. Electrical stimulation and acupoint ST36 may have synergistic effects on CIA.

  19. Adaptation of innate lymphoid cells to nutrient deprivation promotes type 2 barrier immunity

    Survival of the host relies on the establishment of site-specific barrier defense tailored to constrain pressures imposed by commensal and parasitic exposures. The host is confronted with the additional challenge of maintaining barrier immunity in fluctuating states of dietary availability, yet how ...

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

    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 C3

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

    Chris A Kieslich

    Full Text Available 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 C3

  2. NF-κB Functions in Tumor Initiation by Suppressing the Surveillance of Both Innate and Adaptive Immune Cells

    David J. Wang

    2014-10-01

    Full Text Available NF-κB is considered a major contributor to tumor development, but how this factor functions in the initial stages of oncogenesis is not clear. In a model of Ras-induced transformation, we probed NF-κB function as preneoplastic cells formed tumors in mice. As previously shown, the p65 subunit of NF-κB acts as a tumor suppressor in normal cells by sustaining senescence following DNA damage. Our current data reveal that, following immortalization, p65 switches to an oncogene by counteracting the surveillance properties of immune cells. NF-κB exerts this effect by protecting transformed cells against macrophage-derived proapoptotic factors, tumor necrosis factor, and nitric oxide. Additionally, NF-κB acts through transforming growth factor beta (TGF-β to mitigate T cell cytotoxicity and other factors to expand myeloid-derived suppressor cells. Together, these data suggest that NF-κB functions in the early stages of transformation by suppressing immune surveillance of both innate and adaptive immune cells, information that may be useful for targeted immunotherapies.

  3. Dual-Track Clearance of Circulating Bacteria Balances Rapid Restoration of Blood Sterility with Induction of Adaptive Immunity.

    Broadley, Steven P; Plaumann, Ann; Coletti, Raffaele; Lehmann, Christin; Wanisch, Andreas; Seidlmeier, Amelie; Esser, Knud; Luo, Shanshan; Rämer, Patrick C; Massberg, Steffen; Busch, Dirk H; van Lookeren Campagne, Menno; Verschoor, Admar

    2016-07-13

    Efficient clearance of bacteremia prevents life-threatening disease. Platelet binding to intravascular bacteria, a process involving platelet glycoprotein GPIb and bacterial opsonization with activated complement C3, influences blood clearance and anti-infective immunity. Using intravital microscopy of the bloodstream of mice infected with Listeria monocytogenes, we show that bacterial clearance is not a uniform process but a "dual-track" mechanism consisting of parallel "fast" and "slow" pathways. "Slow clearance" is regulated by time-dependent bacterial opsonization, stochastic platelet binding, and capture of bacteria-platelet-complexes via the complement receptor of the immunoglobulin superfamily, CRIg. The mechanism spares some bacteria from "fast clearance" and rapid destruction in the liver via Kupffer cell scavenger receptors, keeping them available for adaptive immunity induction by splenic CD8α(+) dendritic cells. We consistently find "fast" and "slow" clearance patterns for a broad panel of other Gram+ and Gram- bacteria. Thus, dual-track clearance balances rapid restoration of blood sterility with induction of specific antibacterial immunity. PMID:27345696

  4. Long Lasting Local and Systemic Inflammation after Cerebral Hypoxic ischemia in Newborn Mice

    Max Winerdal; Malin Elisabeth Winerdal; Johan Kinn; Vijay Urmaliya; Ola Winqvist; Ulrika Adén

    2012-01-01

    BACKGROUND: Hypoxic ischemia (HI) is an important cause of neonatal brain injury and subsequent inflammation affects neurological outcome. In this study we performed investigations of systemic and local activation states of inflammatory cells from innate and adaptive immunity at different time points after neonatal HI brain injury in mice. METHODOLOGY/PRINCIPAL FINDINGS: We developed a multiplex flow cytometry based method combined with immunohistochemistry to investigate cellular immune resp...

  5. MALT1 Protease Activity Is Required for Innate and Adaptive Immune Responses.

    Jong W Yu

    Full Text Available CARMA-BCL10-MALT1 signalosomes play important roles in antigen receptor signaling and other pathways. Previous studies have suggested that as part of this complex, MALT1 functions as both a scaffolding protein to activate NF-κB through recruitment of ubiquitin ligases, and as a protease to cleave and inactivate downstream inhibitory signaling proteins. However, our understanding of the relative importance of these two distinct MALT1 activities has been hampered by a lack of selective MALT1 protease inhibitors with suitable pharmacologic properties. To fully investigate the role of MALT1 protease activity, we generated mice homozygous for a protease-dead mutation in MALT1. We found that some, but not all, MALT1 functions in immune cells were dependent upon its protease activity. Protease-dead mice had defects in the generation of splenic marginal zone and peritoneal B1 B cells. CD4+ and CD8+ T cells displayed decreased T cell receptor-stimulated proliferation and IL-2 production while B cell receptor-stimulated proliferation was partially dependent on protease activity. In dendritic cells, stimulation of cytokine production through the Dectin-1, Dectin-2, and Mincle C-type lectin receptors was also found to be partially dependent upon protease activity. In vivo, protease-dead mice had reduced basal immunoglobulin levels, and showed defective responses to immunization with T-dependent and T-independent antigens. Surprisingly, despite these decreased responses, MALT1 protease-dead mice, but not MALT1 null mice, developed mixed inflammatory cell infiltrates in multiple organs, suggesting MALT1 protease activity plays a role in immune homeostasis. These findings highlight the importance of MALT1 protease activity in multiple immune cell types, and in integrating immune responses in vivo.

  6. Opinion: Interactions of innate and adaptive lymphocytes

    Gasteiger, Georg; Rudensky, Alexander Y.

    2014-01-01

    Innate lymphocytes, including natural killer (NK) cells and the recently discovered innate lymphoid cells (ILCs) have crucial roles during infection, tissue injury and inflammation. Innate signals regulate the activation and homeostasis of innate lymphocytes. Less well understood is the contribution of the adaptive immune system to the orchestration of innate lymphocyte responses. We review our current understanding of the interactions between adaptive and innate lymphocytes, and propose a mo...

  7. Differential effects of interleukin-17 receptor signaling on innate and adaptive immunity during central nervous system bacterial infection

    Vidlak Debbie

    2012-06-01

    Full Text Available Abstract Although IL-17A (commonly referred to as IL-17 has been implicated in the pathogenesis of central nervous system (CNS autoimmune disease, its role during CNS bacterial infections remains unclear. To evaluate the broader impact of IL-17 family members in the context of CNS infection, we utilized IL-17 receptor (IL-17R knockout (KO mice that lack the ability to respond to IL-17, IL-17F and IL-17E (IL-25. In this article, we demonstrate that IL-17R signaling regulates bacterial clearance as well as natural killer T (NKT cell and gamma-delta (γδ T cell infiltrates during Staphylococcus aureus-induced brain abscess formation. Specifically, when compared with wild-type (WT animals, IL-17R KO mice exhibited elevated bacterial burdens at days 7 and 14 following S. aureus infection. Additionally, IL-17R KO animals displayed elevated neutrophil chemokine production, revealing the ability to compensate for the lack of IL-17R activity. Despite these differences, innate immune cell recruitment into brain abscesses was similar in IL-17R KO and WT mice, whereas IL-17R signaling exerted a greater influence on adaptive immune cell recruitment. In particular, γδ T cell influx was increased in IL-17R KO mice at day 7 post-infection. In addition, NK1.1high infiltrates were absent in brain abscesses of IL-17R KO animals and, surprisingly, were rarely detected in the livers of uninfected IL-17R KO mice. Although IL-17 is a key regulator of neutrophils in other infection models, our data implicate an important role for IL-17R signaling in regulating adaptive immunity during CNS bacterial infection.

  8. Sterile inflammation - do innate lymphoid cell subsets play a role?

    Walsh, Patrick

    2012-01-01

    PUBLISHED The recent identification of several novel innate lymphoid cell (iLC) subsets has increased our understanding of the mechanisms which link the innate and adaptive immune systems. While the contribution of these subsets toward the pathogenesis of human disease remains largely to be determined, it seems likely that they will play a particularly important role in sterile inflammatory settings where the innate response is seen as a critical mediator of inflammation. Several recent st...

  9. Immunomodulatory effects and adaptive immune response to daratumumab in multiple myeloma

    Krejcik, Jakub; Casneuf, T.; Nijhof, I.;

    2015-01-01

    assays. T-cell subpopulation counts were modelled over time with linear mixed modelling. Two group comparisons were performed using non-parametric Wilcoxon rank sum tests. Results: Data from 148 patients receiving 16 mg/kg DARA in GEN501 (n = 42) and Sirius (n = 106) were analyzed for changes in immune......Introduction: Daratumumab (DARA) is a novel human monoclonal antibody that targets CD38, a protein that is highly expressed on multiple myeloma (MM) cells. DARA acts through multiple immune effector-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cell......-mediated cytotoxicity, and antibody-dependent cellular phagocytosis. In two clinical studies (NCT00574288 [GEN501] and NCT01985126 [Sirius]) of DARA monotherapy in patients with relapsed and refractory MM, overall response rates were 36% and 29%, respectively. CD38 is highly expressed in myeloma cells but also...

  10. Influence of Phthalates on in vitro Innate and Adaptive Immune Responses

    Hansen, Juliana Frohnert; Nielsen, Claus Henrik; Brorson, Marianne Møller; Frederiksen, Hanne; Hartoft-Nielsen, Marie-Louise; Rasmussen, Åse Krogh; Bendtzen, Klaus; Feldt-Rasmussen, Ulla

    2015-01-01

    Phthalates are a group of endocrine disrupting chemicals, suspected to influence the immune system. The aim of this study was to investigate the influence of phthalates on cytokine secretion from human peripheral blood mononuclear cells. Escherichia coli lipopolysaccharide and phytohemagglutinin-P were used for stimulation of monocytes/macrophages and T cells, respectively. Cells were exposed for 20 to 22 hours to either di-ethyl, di-n-butyl or mono-n-butyl phthalate at two different concentr...

  11. 5-Lipoxygenase Deficiency Impairs Innate and Adaptive Immune Responses during Fungal Infection

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

    2012-01-01

    5-Lipoxygenase-derived products have been implicated in both the inhibition and promotion of chronic infection. Here, we sought to investigate the roles of endogenous 5-lipoxygenase products and exogenous leukotrienes during Histoplasma capsulatum infection in vivo and in vitro. 5-LO deficiency led to increased lung CFU, decreased nitric oxide production and a deficient primary immune response during active fungal infection. Moreover, H. capsulatum-infected 5-LO(-/-) mice showed an intense in...

  12. Has the microbiota played a critical role in the evolution of the adaptive immune system?

    Lee, Yun Kyung; Mazmanian, Sarkis K.

    2010-01-01

    Although microbes have been classically viewed as pathogens, it is now well established that the majority of host-bacterial interactions are symbiotic. During development and into adulthood, gut bacteria shape the tissues, cells and molecular profile of our gastrointestinal immune system. This partnership, forged over many millennia of co-evolution, is based on a molecular exchange involving bacterial signals that are recognized by host receptors to mediate beneficial outcomes for both microb...

  13. Richness and diversity of mammalian fungal communities shape innate and adaptive immunity in health and disease

    Rizzetto, Lisa; De Filippo, Carlotta; Cavalieri, Duccio

    2014-01-01

    Human holobiomes are networks of mutualistic interactions between human cells and complex communities of bacteria and fungi that colonize the human body. The immune system must tolerate colonization with commensal bacteria and fungi but defend against invasion by either organism. Molecular ecological surveys of the human prokaryotic microbiota performed to date have revealed a remarkable degree of bacterial diversity and functionality. However, there is a dearth of information regarding the e...

  14. The isolator piglet: a model for studying the development of adaptive immunity

    Butler, J. E.; Šinkora, Marek

    2007-01-01

    Roč. 39, 1-3 (2007), s. 33-51. ISSN 0257-277X R&D Projects: GA ČR GA524/07/0087; GA ČR GA523/07/0088; GA AV ČR IAA5020303 Institutional research plan: CEZ:AV0Z50200510 Keywords : neonatal development * colonization * immune homeostasis Subject RIV: EE - Microbiology, Virology Impact factor: 2.364, year: 2007

  15. HIV-1 Adaptation to Antigen Processing Results in Population-Level Immune Evasion and Affects Subtype Diversification

    Stefan Tenzer

    2014-04-01

    Full Text Available The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8+ T cell responses to two HIV-Gag regions are uniquely associated with delayed disease progression only in patients expressing a few rare HLA class I variants when these regions encode epitopes presented by ∼30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ∼60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of intrapatient adaptations, is predictable, facilitates viral subtype diversification, and increases global HIV diversity. Because low epitope abundance is associated with infrequent and weak T cell responses, this most likely results in both population-level immune evasion and inadequate responses in most people vaccinated with natural HIV-1 sequence constructs. Our results suggest that artificial sequence modifications at subtype-specific positions in vitro could refocus and reverse the poor immunogenicity of HIV proteins.

  16. Immune responses to improving welfare.

    Berghman, L R

    2016-09-01

    The relationship between animal welfare and the immune status of an animal has a complex nature. Indeed, the intuitive notion that "increased vigilance of the immune system is by definition better" because it is expected to better keep the animal healthy, does not hold up under scrutiny. This is mostly due to the fact that the immune system consists of 2 distinct branches, the innate and the adaptive immune system. While they are intimately intertwined and synergistic in the living organism, they are profoundly different in their costs, both in terms of performance and wellbeing. In contrast to the adaptive immune system, the action of the innate immune system has a high metabolic cost as well as undesirable behavioral consequences. When a pathogen breaches the first line of defense (often a mucosal barrier), that organism's molecular signature is recognized by resident macrophages. The macrophages respond by releasing a cocktail of pro-inflammatory cytokines (including interleukin-1 and -6) that signal the brain via multiple pathways (humoral as well as neural) of the ongoing peripheral innate immune response. The behavioral response to the release of proinflammatory cytokines, known as "sickness behavior," includes nearly all the behavioral aspects that are symptomatic for clinical depression in humans. Hence, undesired innate immune activity, such as chronic inflammation, needs to be avoided by the industry. From an immunological standpoint, one of the most pressing poultry industry needs is the refinement of our current veterinary vaccine arsenal. The response to a vaccine, especially to a live attenuated vaccine, is often a combination of innate and adaptive immune activities, and the desired immunogenicity comes at the price of high reactogenicity. The morbidity, albeit limited and transient, caused by live vaccines against respiratory diseases and coccidiosis are good examples. Thankfully, the advent of various post-genomics technologies, such as DNA

  17. Let-7b is involved in the inflammation and immune responses associated with Helicobacter pylori infection by targeting Toll-like receptor 4.

    Gui-gen Teng

    related to the inflammation and immune responses in H.pylori infection.

  18. New Digital Signature Scheme Attaining Immunity to Adaptive Chosen Message Attack

    ZHU Huafei

    2001-01-01

    A new signature provably secureagainst adaptive chosen message attack is developedin this report. It is state-free and the proof of secu-rity is based on "strong RSA (Rivest-shamir-adleman)assumption, collision free hash algorithm as well as in-tractability of" discrete logarithm problem.

  19. Topical CpG Oligodeoxynucleotide Adjuvant Enhances the Adaptive Immune Response against Influenza A Infections.

    Cheng, Wing Ki; Plumb, Adam William; Lai, Jacqueline Cheuk-Yan; Abraham, Ninan; Dutz, Jan Peter

    2016-01-01

    Current influenza vaccines generate humoral immunity, targeting highly variable epitopes and thus fail to achieve long-term protection. T cells recognize and respond to several highly conserved epitopes across influenza serotypes. A strategy of raising strong cytotoxic T cell memory responses to epitopes conserved across serotypes would provide cross serotype protection, eliminating the need for annual vaccination. We explored the adjuvant potential of epicutaneous (ec) and subcutaneous (sc) delivery of CpG oligodeoxynucleotide in conjunction with sc protein immunization to improve protection against influenza A virus (IAV) infections using a mouse model. We found enhanced long-term protection with epicutaneous CpG ODN (ecCpG) compared to subcutaneous CpG ODN (scCpG) as demonstrated by reduced viral titers in the lungs. This correlated with increased antigen-specific CD8 T cells in the airways and the lungs. The memory T cell response after immunization with ecCpG adjuvant was comparable to memory response by priming with IAV infection in the lungs. In addition, ecCpG was more efficient than scCpG in inducing the generation of IFN-γ producing CD4 T cells. The adjuvant effect of ecCpG was accompanied with its ability to modulate tissue-homing molecules on T cells that may direct them to the site of infection. Together, this work provides evidence for using ecCpG to induce strong antibody and memory T cell responses to confer protection against IAV infection. PMID:27524984

  20. Parainflammation, chronic inflammation, and age-related macular degeneration.

    Chen, Mei; Xu, Heping

    2015-11-01

    Inflammation is an adaptive response of the immune system to noxious insults to maintain homeostasis and restore functionality. The retina is considered an immune-privileged tissue as a result of its unique anatomic and physiologic properties. During aging, the retina suffers from a low-grade chronic oxidative insult, which sustains for decades and increases in level with advancing age. As a result, the retinal innate-immune system, particularly microglia and the complement system, undergoes low levels of activation (parainflammation). In many cases, this parainflammatory response can maintain homeostasis in the healthy aging eye. However, in patients with age-related macular degeneration, this parainflammatory response becomes dysregulated and contributes to macular damage. Factors contributing to the dysregulation of age-related retinal parainflammation include genetic predisposition, environmental risk factors, and old age. Dysregulated parainflammation (chronic inflammation) in age-related macular degeneration damages the blood retina barrier, resulting in the breach of retinal-immune privilege, leading to the development of retinal lesions. This review discusses the basic principles of retinal innate-immune responses to endogenous chronic insults in normal aging and in age-related macular degeneration and explores the difference between beneficial parainflammation and the detrimental chronic inflammation in the context of age-related macular degeneration. PMID:26292978

  1. Enhancing Artificial Bee Colony Algorithm with Self-Adaptive Searching Strategy and Artificial Immune Network Operators for Global Optimization

    Tinggui Chen

    2014-01-01

    Full Text Available Artificial bee colony (ABC algorithm, inspired by the intelligent foraging behavior of honey bees, was proposed by Karaboga. It has been shown to be superior to some conventional intelligent algorithms such as genetic algorithm (GA, artificial colony optimization (ACO, and particle swarm optimization (PSO. However, the ABC still has some limitations. For example, ABC can easily get trapped in the local optimum when handing in functions that have a narrow curving valley, a high eccentric ellipse, or complex multimodal functions. As a result, we proposed an enhanced ABC algorithm called EABC by introducing self-adaptive searching strategy and artificial immune network operators to improve the exploitation and exploration. The simulation results tested on a suite of unimodal or multimodal benchmark functions illustrate that the EABC algorithm outperforms ACO, PSO, and the basic ABC in most of the experiments.

  2. Enhancing artificial bee colony algorithm with self-adaptive searching strategy and artificial immune network operators for global optimization.

    Chen, Tinggui; Xiao, Renbin

    2014-01-01

    Artificial bee colony (ABC) algorithm, inspired by the intelligent foraging behavior of honey bees, was proposed by Karaboga. It has been shown to be superior to some conventional intelligent algorithms such as genetic algorithm (GA), artificial colony optimization (ACO), and particle swarm optimization (PSO). However, the ABC still has some limitations. For example, ABC can easily get trapped in the local optimum when handing in functions that have a narrow curving valley, a high eccentric ellipse, or complex multimodal functions. As a result, we proposed an enhanced ABC algorithm called EABC by introducing self-adaptive searching strategy and artificial immune network operators to improve the exploitation and exploration. The simulation results tested on a suite of unimodal or multimodal benchmark functions illustrate that the EABC algorithm outperforms ACO, PSO, and the basic ABC in most of the experiments. PMID:24772023

  3. A chromosomally encoded virulence factor protects the Lyme disease pathogen against host-adaptive immunity.

    Xiuli Yang

    2009-03-01

    Full Text Available Borrelia burgdorferi, the bacterial pathogen of Lyme borreliosis, differentially expresses select genes in vivo, likely contributing to microbial persistence and disease. Expression analysis of spirochete genes encoding potential membrane proteins showed that surface-located membrane protein 1 (lmp1 transcripts were expressed at high levels in the infected murine heart, especially during early stages of infection. Mice and humans with diagnosed Lyme borreliosis also developed antibodies against Lmp1. Deletion of lmp1 severely impaired the pathogen's ability to persist in diverse murine tissues including the heart, and to induce disease, which was restored upon chromosomal complementation of the mutant with the lmp1 gene. Lmp1 performs an immune-related rather than a metabolic function, as its deletion did not affect microbial persistence in immunodeficient mice, but significantly decreased spirochete resistance to the borreliacidal effects of anti-B. burgdorferi sera in a complement-independent manner. These data demonstrate the existence of a virulence factor that helps the pathogen evade host-acquired immune defense and establish persistent infection in mammals.

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

    Volkov, I.; Pepin, KM; Lloyd-Smith, JO; Banavar, JR; Grenfell, BT

    2010-01-01

    The evolution of viruses to escape prevailing host immunity involves selection at multiple integrative scales, from within-host viral and immune kinetics to the host population level. In order to understand how viral immune escape occurs, we develop an analytical framework that links the dynamical nature of immunity and viral variation across these scales. Our epidemiological model incorporates within-host viral evolutionary dynamics for a virus that causes acute infections (e.g. influenza an...

  5. Biomarker Analysis Revealed Distinct Profiles of Innate and Adaptive Immunity in Infants with Ocular Lesions of Congenital Toxoplasmosis

    Machado, Anderson Silva; Carneiro, Ana Carolina Aguiar Vasconcelos; Béla, Samantha Ribeiro; Andrade, Gláucia Manzan Queiroz; Vasconcelos-Santos, Daniel Vitor; Januário, José Nélio; Coelho-dos-Reis, Jordana G.; Ferro, Eloisa Amália Vieira; Teixeira-Carvalho, Andréa; Vitor, Ricardo Wagner Almeida; Martins-Filho, Olindo Assis; —UFMG-CTBG, UFMG Congenital Toxoplasmosis Brazilian Group

    2014-01-01

    Toxoplasma gondii is the main infectious cause of human posterior retinochoroiditis, the most frequent clinical manifestation of congenital toxoplasmosis. This investigation was performed after neonatal screening to identify biomarkers of immunity associated with immunopathological features of the disease by flow cytometry. The study included infected infants without NRL and with retinochoroidal lesions (ARL, ACRL, and CRL) as well as noninfected individuals (NI). Our data demonstrated that leukocytosis, with increased monocytes and lymphocytes, was a relevant hematological biomarker of ARL. Immunophenotypic analysis also revealed expansion of CD14+CD16+HLA-DRhigh monocytes and CD56dim cytotoxic NK-cells in ARL. Moreover, augmented TCRγδ+ and CD8+ T-cell counts were apparently good biomarkers of morbidity. Biomarker network analysis revealed that complex and intricated networks underscored the negative correlation of monocytes with NK- and B-cells in NRL. The remarkable lack of connections involving B-cells and a relevant shift of NK-cell connections from B-cells toward T-cells observed in ARL were outstanding. A tightly connected biomarker network was observed in CRL, with relevant connections of NK- and CD8+ T-cells with a broad range of cell subsets. Our findings add novel elements to the current knowledge on the innate and adaptive immune responses in congenital toxoplasmosis. PMID:25328286

  6. Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system

    Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS). However, VSV encephalitis is not invariably fatal, suggesting that the CNS may contain a professional antigen-presenting cell (APC) capable of inducing or propagating a protective antiviral immune response. To examine this possibility, we first characterized the cellular elements that infiltrate the brain as well as the activation status of resident microglia in the brains of normal and transgenic mice acutely ablated of peripheral dendritic cells (DCs) in vivo. VSV encephalitis was characterized by a pronounced infiltrate of myeloid cells (CD45highCD11b+) and CD8+ T cells containing a subset that was specific for the immunodominant VSV nuclear protein epitope. This T cell response correlated temporally with a rapid and sustained upregulation of MHC class I expression on microglia, whereas class II expression was markedly delayed. Ablation of peripheral DCs profoundly inhibited the inflammatory response as well as infiltration of virus-specific CD8+ T cells. Unexpectedly, the VSV-induced interferon-gamma (IFN-γ) response in the CNS remained intact in DC-deficient mice. Thus, both the inflammatory and certain components of the adaptive primary antiviral immune response in the CNS are dependent on peripheral DCs in vivo.

  7. Long-term effects of early life microbiota disturbance on adaptive immunity in laying hens.

    Simon, K; Verwoolde, M B; Zhang, J; Smidt, H; de Vries Reilingh, G; Kemp, B; Lammers, A

    2016-07-01

    Due to an interplay between intestinal microbiota and immune system, disruption of intestinal microbiota composition during immune development may have consequences for immune responses later in life. The present study investigated the effects of antibiotic treatment in the first weeks of life on the specific antibody response later in life in chickens. Layer chicks received an antibiotic cocktail consisting of vancomycin, neomycin, metronidazole, and amphotericin-B by oral gavage every 12 h, and ampicillin and colistin in drinking water for the first week of life. After the first week of life, chicks received ampicillin and colistin in drinking water for two more weeks. Control birds received no antibiotic cocktail and plain drinking water. Fecal microbiota composition was determined during antibiotic treatment (d 8 and 22), two weeks after cessation of antibiotic treatment (d 36), and at the end of the experimental period at d 175 using a 16S ribosomal RNA gene targeted microarray, the Chicken Intestinal Tract Chip (ChickChip). During antibiotic treatment fecal microbiota composition differed strongly between treatment groups. Fecal microbiota of antibiotic treated birds consisted mainly of Proteobacteria, and in particular E.coli, whereas fecal microbiota of control birds consisted mainly of Firmicutes, such as lactobacilli and clostridia. Two weeks after cessation of antibiotic treatment fecal microbiota composition of antibiotic treated birds had recovered and was similar to that of control birds. On d 105, 12 weeks after cessation of antibiotic treatment, chicks of both treatment groups received an intra-tracheal lipopolysaccharide (LPS)/human serum albumin (HuSA) challenge. Antibody titers against LPS and HuSA were measured 10 days after administration of the challenge. While T cell independent antibody titers (LPS) were not affected by antibiotic treatment, antibiotic treated birds showed lower T cell dependent antibody titers (HuSA) compared with control

  8. CRISPR-Cas Adaptive Immune Systems of the Sulfolobales: Unravelling Their Complexity and Diversity

    Roger A. Garrett

    2015-03-01

    Full Text Available The Sulfolobales have provided good model organisms for studying CRISPR-Cas systems of the crenarchaeal kingdom of the archaea. These organisms are infected by a wide range of exceptional archaea-specific viruses and conjugative plasmids, and their CRISPR-Cas systems generally exhibit extensive structural and functional diversity. They carry large and multiple CRISPR loci and often multiple copies of diverse Type I and Type III interference modules as well as more homogeneous adaptation modules. These acidothermophilic organisms have recently provided seminal insights into both the adaptation process, the diverse modes of interference, and their modes of regulation. The functions of the adaptation and interference modules tend to be loosely coupled and the stringency of the crRNA-DNA sequence matching during DNA interference is relatively low, in contrast to some more streamlined CRISPR-Cas systems of bacteria. Despite this, there is evidence for a complex and differential regulation of expression of the diverse functional modules in response to viral infection. Recent work also supports critical roles for non-core Cas proteins, especially during Type III-directed interference, and this is consistent with these proteins tending to coevolve with core Cas proteins. Various novel aspects of CRISPR-Cas systems of the Sulfolobales are considered including an alternative spacer acquisition mechanism, reversible spacer acquisition, the formation and significance of antisense CRISPR RNAs, and a novel mechanism for avoidance of CRISPR-Cas defense. Finally, questions regarding the basis for the complexity, diversity, and apparent redundancy, of the intracellular CRISPR-Cas systems are discussed.

  9. Chronic Inflammation in Cancer Development

    Multhoff, Gabriele; Molls, Michael; Radons, Jürgen

    2012-01-01

    Chronic inflammatory mediators exert pleiotropic effects in the development of cancer. On the one hand, inflammation favors carcinogenesis, malignant transformation, tumor growth, invasion, and metastatic spread; on the other hand inflammation can stimulate immune effector mechanisms that might limit tumor growth. The link between cancer and inflammation depends on intrinsic and extrinsic pathways. Both pathways result in the activation of transcription factors such as NF-κB, STAT-3, and HIF-...

  10. Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice

    The lung response to radiation exposure can involve an immediate or early reaction to the radiation challenge, including cell death and an initial immune reaction, and can be followed by a tissue injury response, of pneumonitis or fibrosis, to this acute reaction. Herein, we aimed to determine whether markers of the initial immune response, measured within days of radiation exposure, are correlated with the lung tissue injury responses occurring weeks later. Inbred strains of mice known to be susceptible (KK/HIJ, C57BL/6J, 129S1/SvImJ) or resistant (C3H/HeJ, A/J, AKR/J) to radiation-induced pulmonary fibrosis and to vary in time to onset of respiratory distress post thoracic irradiation (from 10–23 weeks) were studied. Mice were untreated (controls) or received 18 Gy whole thorax irradiation and were euthanized at 6 h, 1d or 7 d after radiation treatment. Pulmonary CD4+ lymphocytes, bronchoalveolar cell profile & cytokine level, and serum cytokine levels were assayed. Thoracic irradiation and inbred strain background significantly affected the numbers of CD4+ cells in the lungs and the bronchoalveolar lavage cell differential of exposed mice. At the 7 day timepoint greater numbers of pulmonary Th1 and Th17 lymphocytes and reduced lavage interleukin17 and interferonγ levels were significant predictors of late stage fibrosis. Lavage levels of interleukin-10, measured at the 7 day timepoint, were inversely correlated with fibrosis score (R = −0.80, p = 0.05), while serum levels of interleukin-17 in control mice significantly correlated with post irradiation survival time (R = 0.81, p = 0.04). Lavage macrophage, lymphocyte or neutrophil counts were not significantly correlated with either of fibrosis score or time to respiratory distress in the six mouse strains. Specific cytokine and lymphocyte levels, but not strain dependent lavage cell profiles, were predictive of later radiation-induced lung injury in this panel of inbred strains. The online version of this

  11. Enhancement of human adaptive immune responses by administration of a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensis

    Pedersen, Morten Løbner; Walsted, Anette; Larsen, Rune;

    2008-01-01

    The effect of consumption of Immulina, a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensis, on adaptive immune responses was investigated by evaluation of changes in leukocyte responsiveness to two foreign recall antigens, Candida albicans (CA) and tetanus...

  12. Inhibition of adaptive immune responses leads to a fatal clinical outcome in SIV-infected pigtailed macaques but not vervet African green monkeys.

    Jörn E Schmitz

    2009-12-01

    Full Text Available African green monkeys (AGM and other natural hosts for simian immunodeficiency virus (SIV do not develop an AIDS-like disease following SIV infection. To evaluate differences in the role of SIV-specific adaptive immune responses between natural and nonnatural hosts, we used SIV(agmVer90 to infect vervet AGM and pigtailed macaques (PTM. This infection results in robust viral replication in both vervet AGM and pigtailed macaques (PTM but only induces AIDS in the latter species. We delayed the development of adaptive immune responses through combined administration of anti-CD8 and anti-CD20 lymphocyte-depleting antibodies during primary infection of PTM (n = 4 and AGM (n = 4, and compared these animals to historical controls infected with the same virus. Lymphocyte depletion resulted in a 1-log increase in primary viremia and a 4-log increase in post-acute viremia in PTM. Three of the four PTM had to be euthanized within 6 weeks of inoculation due to massive CMV reactivation and disease. In contrast, all four lymphocyte-depleted AGM remained healthy. The lymphocyte-depleted AGM showed only a trend toward a prolongation in peak viremia but the groups were indistinguishable during chronic infection. These data show that adaptive immune responses are critical for controlling disease progression in pathogenic SIV infection in PTM. However, the maintenance of a disease-free course of SIV infection in AGM likely depends on a number of mechanisms including non-adaptive immune mechanisms.

  13. The pattern recognition molecule ficolin-1 exhibits differential binding to lymphocyte subsets, providing a novel link between innate and adaptive immunity

    Genster, Ninette; Ma, Ying Jie; Munthe-Fog, Lea; Garred, Peter

    2014-01-01

    -lymphocyte interaction occurred via the pathogen-recognition domain of ficolin-1 to sialic acid on the cell surface. Thus, the differential binding of ficolin-1 to lymphocyte subsets suggests ficolin-1 as a novel link between innate and adaptive immunity. Our results provide new insight about the recognition properties...

  14. Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer.

    Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Matsumoto, Yoshihiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

    2016-05-14

    The incidence of pancreatic ductal adenocarcinoma (PDA) is on the rise, and the prognosis is extremely poor because PDA is highly aggressive and notoriously difficult to treat. Although gemcitabine- or 5-fluorouracil-based chemotherapy is typically offered as a standard of care, most patients do not survive longer than 1 year. Therefore, the development of alternative therapeutic approaches for patients with PDA is imperative. As PDA cells express numerous tumor-associated antigens that are suitable vaccine targets, one promising treatment approach is cancer vaccines. During the last few decades, cell-based cancer vaccines have offered encouraging results in preclinical studies. Cell-based cancer vaccines are mainly generated by presenting whole tumor cells or dendritic cells to cells of the immune system. In particular, several clinical trials have explored cell-based cancer vaccines as a promising therapeutic approach for patients with PDA. Moreover, chemotherapy and cancer vaccines can synergize to result in increased efficacies in patients with PDA. In this review, we will discuss both the effect of cell-based cancer vaccines and advances in terms of future strategies of cancer vaccines for the treatment of PDA patients. PMID:27182156

  15. Gene expression profiling of Gram-negative bacteria-induced inflammation in human whole blood: The role of complement and CD14-mediated innate immune response.

    Lau, Corinna; Olstad, Ole Kristoffer; Holden, Marit; Nygård, Ståle; Fure, Hilde; Lappegård, Knut Tore; Brekke, Ole-Lars; Espevik, Terje; Hovig, Eivind; Mollnes, Tom Eirik

    2015-09-01

    Non-sterile pathogen-induced sepsis and sterile inflammation like in trauma or ischemia-reperfusion injury may both coincide with the life threatening systemic inflammatory response syndrome and multi-organ failure. Consequently, there is an urgent need for specific biomarkers in order to distinguish sepsis from sterile conditions. The overall aim of this study was to uncover putative sepsis biomarkers and biomarker pathways, as well as to test the efficacy of combined inhibition of innate immunity key players complement and Toll-like receptor co-receptor CD14 as a possible therapeutic regimen for sepsis. We performed whole blood gene expression analyses using microarray in order to profile Gram-negative bacteria-induced inflammatory responses in an ex vivo human whole blood model. The experiments were performed in the presence or absence of inhibitors of complement proteins (C3 and CD88 (C5a receptor 1)) and CD14, alone or in combination. In addition, we used blood from a C5-deficient donor. Anti-coagulated whole blood was challenged with heat-inactivated Escherichia coli for 2 h, total RNA was isolated and microarray analyses were performed on the Affymetrix GeneChip Gene 1.0 ST Array platform. The initial experiments were performed in duplicates using blood from two healthy donors. C5-deficiency is very rare, and only one donor could be recruited. In order to increase statistical power, a technical replicate of the C5-deficient samples was run. Subsequently, log2-transformed intensities were processed by robust multichip analysis and filtered using a threshold of four. In total, 73 microarray chips were run and analyzed. The normalized and filtered raw data have been deposited in NCBI's Gene Expression Omnibus (GEO) and are accessible with GEO Series accession number GSE55537. Linear models for microarray data were applied to estimate fold changes between data sets and the respective multiple testing adjusted p-values (FDR q-values). The interpretation of the

  16. Gene expression profiling of Gram-negative bacteria-induced inflammation in human whole blood: The role of complement and CD14-mediated innate immune response

    Corinna Lau

    2015-09-01

    Full Text Available Non-sterile pathogen-induced sepsis and sterile inflammation like in trauma or ischemia–reperfusion injury may both coincide with the life threatening systemic inflammatory response syndrome and multi-organ failure. Consequently, there is an urgent need for specific biomarkers in order to distinguish sepsis from sterile conditions. The overall aim of this study was to uncover putative sepsis biomarkers and biomarker pathways, as well as to test the efficacy of combined inhibition of innate immunity key players complement and Toll-like receptor co-receptor CD14 as a possible therapeutic regimen for sepsis. We performed whole blood gene expression analyses using microarray in order to profile Gram-negative bacteria-induced inflammatory responses in an ex vivo human whole blood model. The experiments were performed in the presence or absence of inhibitors of complement proteins (C3 and CD88 (C5a receptor 1 and CD14, alone or in combination. In addition, we used blood from a C5-deficient donor. Anti-coagulated whole blood was challenged with heat-inactivated Escherichia coli for 2 h, total RNA was isolated and microarray analyses were performed on the Affymetrix GeneChip Gene 1.0 ST Array platform. The initial experiments were performed in duplicates using blood from two healthy donors. C5-deficiency is very rare, and only one donor could be recruited. In order to increase statistical power, a technical replicate of the C5-deficient samples was run. Subsequently, log2-transformed intensities were processed by robust multichip analysis and filtered using a threshold of four. In total, 73 microarray chips were run and analyzed. The normalized and filtered raw data have been deposited in NCBI's Gene Expression Omnibus (GEO and are accessible with GEO Series accession number GSE55537. Linear models for microarray data were applied to estimate fold changes between data sets and the respective multiple testing adjusted p-values (FDR q-values. The

  17. TLR2-independent induction and regulation of chronic intestinal inflammation.

    Boulard, Olivier; Asquith, Mark J; Powrie, Fiona; Maloy, Kevin J

    2010-02-01

    Interactions between the intestinal microflora and host innate immune receptors play a critical role in intestinal homeostasis. Several studies have shown that TLR2 can modulate inflammatory responses in the gut. TLR2 signals enhance tight junction formation and fortify the epithelial barrier, and may play a crucial role in driving acute inflammatory responses towards intestinal bacterial pathogens. In addition, TLR2 agonists can have direct effects on both Th1 cells and Treg. To define the role of TLR2 in the induction and regulation of chronic intestinal inflammation we examined the effects of TLR2 deletion on several complementary models of inflammatory bowel disease. Our results show that TLR2 signals are not required for the induction of chronic intestinal inflammation by either innate or adaptive immune responses. We further show that TLR2(-/-) mice harbor normal numbers of Foxp3(+) Treg that are able to suppress intestinal inflammation as effectively as their WT counterparts. We also did not find any intrinsic role for TLR2 for pathogenic effector T-cell responses in the gut. Thus, in contrast to their role in acute intestinal inflammation and repair, TLR2 signals may have a limited impact on the induction and regulation of chronic intestinal inflammation. PMID:19950179

  18. How to Make a Non-Antigenic Protein (Auto) Antigenic: Molecular Complementarity Alters Antigen Processing and Activates Adaptive-Innate Immunity Synergy.

    Root-Bernstein, Robert

    2015-01-01

    Evidence is reviewed that complementary proteins and peptides form complexes with increased antigenicity and/or autoimmunogenicity. Five case studies are highlighted: 1) diphtheria toxin-antitoxin (antibody), which induces immunity to the normally non-antigenic toxin, and autoimmune neuritis; 2) tryptophan peptide of myelin basic protein and muramyl dipeptide ("adjuvant peptide"), which form a complex that induces experimental allergic encephalomyelitis; 3) an insulin and glucagon complex that is far more antigenic than either component individually; 4) various causes of experimental autoimmune myocarditis such as C protein in combination with its antibody, or coxsackie B virus in combination with the coxsackie and adenovirus receptor; 5) influenza A virus haemagglutinin with the outer membrane protein of the Haemophilus influenzae, which increases antigenicity. Several mechanisms cooperate to alter immunogenicity. Complexation alters antigen processing, protecting the components against proteolysis, altering fragmentation and presenting novel antigens to the immune system. Complementary antigens induce complementary adaptive immune responses (complementary antibodies and/or T cell receptors) that produce circulating immune complexes (CIC). CIC stimulate innate immunity. Concurrently, complementary antigens stimulate multiple Toll-like receptors that synergize to over-produce cytokines, which further stimulate adaptive immunity. Thus innate and adaptive immunity form a positive feedback loop. If components of the complex mimic a host protein, then autoimmunity may result. Enhanced antigenicity for production of improved vaccines and/or therapeutic autoimmunity (e.g., against cancer cells) might be achieved by using information from antibody or TCR recognition sites to complement an antigen; by panning for complements in randomized peptide libraries; or using antisense peptide strategies to design complements. PMID:26179268

  19. Characterization of homologous and heterologous adaptive immune responses in porcine reproductive and respiratory syndrome virus infection.

    Díaz, Ivan; Gimeno, Mariona; Darwich, Laila; Navarro, Nuria; Kuzemtseva, Liudmila; López, Sergio; Galindo, Ivan; Segalés, Joaquim; Martín, Margarita; Pujols, Joan; Mateu, Enric

    2012-01-01

    The present study characterized the homologous and heterologous immune response in type-I porcine reproductive and respiratory syndrome virus (PRRSV) infection. Two experiments were conducted: in experiment 1, eight pigs were inoculated with PRRSV strain 3262 and 84 days post-inoculation (dpi) they were challenged with either strain 3262 or strain 3267 and followed for the next 14 days (98 dpi). In experiment 2, eight pigs were inoculated with strain 3267 and challenged at 84 dpi as above. Clinical course, viremia, humoral response (neutralizing and non-neutralizing antibodies, NA) and virus-specific IFN-γ responses (ELISPOT) were evaluated all throughout the study. Serum levels of IL-1, IL-6, IL-8, TNF-α and TGF-β were determined (ELISA) after the second challenge. In experiment 1 primo-inoculation with strain 3262 induced viremia of ≤ 28 days, low titres of homologous NA but strong IFN-γ responses. In contrast, strain 3267 induced longer viremias (up to 56 days), higher NA titres (≤ 6 log2) and lower IFN-γ responses. Inoculation with 3267 produced higher serum IL-8 levels. After the re-challenge at 84 dpi, pigs in experiment 1 developed mostly a one week viremia regardless of the strain used. In experiment 2, neither the homologous nor the heterologous challenge resulted in detectable viremia although PRRSV was present in tonsils of some animals. Homologous re-inoculation with 3267 produced elevated TGF-β levels in serum for 7-14 days but this did not occur with the heterologous re-inoculation. In conclusion, inoculation with different PRRSV strains result in different virological and immunological outcomes and in different degrees of homologous and heterologous protection. PMID:22515169

  20. Characterization of homologous and heterologous adaptive immune responses in porcine reproductive and respiratory syndrome virus infection

    Díaz Ivan

    2012-04-01

    Full Text Available Abstract The present study characterized the homologous and heterologous immune response in type-I porcine reproductive and respiratory syndrome virus (PRRSV infection. Two experiments were conducted: in experiment 1, eight pigs were inoculated with PRRSV strain 3262 and 84 days post-inoculation (dpi they were challenged with either strain 3262 or strain 3267 and followed for the next 14 days (98 dpi. In experiment 2, eight pigs were inoculated with strain 3267 and challenged at 84 dpi as above. Clinical course, viremia, humoral response (neutralizing and non-neutralizing antibodies, NA and virus-specific IFN-γ responses (ELISPOT were evaluated all throughout the study. Serum levels of IL-1, IL-6, IL-8, TNF-α and TGF-β were determined (ELISA after the second challenge. In experiment 1 primo-inoculation with strain 3262 induced viremia of ≤ 28 days, low titres of homologous NA but strong IFN-γ responses. In contrast, strain 3267 induced longer viremias (up to 56 days, higher NA titres (≤ 6 log2 and lower IFN-γ responses. Inoculation with 3267 produced higher serum IL-8 levels. After the re-challenge at 84 dpi, pigs in experiment 1 developed mostly a one week viremia regardless of the strain used. In experiment 2, neither the homologous nor the heterologous challenge resulted in detectable viremia although PRRSV was present in tonsils of some animals. Homologous re-inoculation with 3267 produced elevated TGF-β levels in serum for 7–14 days but this did not occur with the heterologous re-inoculation. In conclusion, inoculation with different PRRSV strains result in different virological and immunological outcomes and in different degrees of homologous and heterologous protection.

  1. Circulating Tumor Cells (CTC) Are Associated with Defects in Adaptive Immunity in Patients with Inflammatory Breast Cancer

    Mego, M; Gao, H; Cohen, EN; Anfossi, S; Giordano, A; Sanda, T; Fouad, TM; De Giorgi, U; Giuliano, M; Woodward, WA; Alvarez, RH; Valero, V; Ueno, NT; Hortobagyi, GN; Cristofanilli, M; Reuben, JM

    2016-01-01

    Background: Circulating tumor cells (CTCs) play a crucial role in tumor dissemination and are prognostic in primary and metastatic breast cancer. Peripheral blood (PB) immune cells contribute to an unfavorable microenvironment for CTC survival. This study aimed to correlate CTCs with the PB T-cell immunophenotypes and functions of patients with inflammatory breast cancer (IBC). Methods: This study included 65 IBC patients treated at the MD Anderson Cancer Center. PB was obtained from patients prior to starting a new line of chemotherapy for CTCs enumeration by CellSearch®, and T cell phenotype and function by flow cytometry; the results were correlated with CTCs and clinical outcome. Results: At least 1 CTC (≥1) or ≥5 CTCs was detected in 61.5% or 32.3% of patients, respectively. CTC count did not correlate with total lymphocytes; however, patients with ≥1 CTC or ≥5 CTCs had lower percentages (%) of CD3+ and CD4+ T cells compared with patients with no CTCs or <5 CTCs, respectively. Patients with ≥1 CTC had a lower percentage of T-cell receptor (TCR)-activated CD8+ T cells synthesizing TNF-α and IFN-γ and a higher percentage of T-regulatory lymphocytes compared to patients without CTCs. In multivariate analysis, tumor grade and % CD3+ T-cells were associated with ≥1 CTC, whereas ≥5 CTC was associated with tumor grade, stage, % CD3+ and % CD4+ T cells, and % TCR-activated CD8 T-cells synthesizing IL-17. Conclusions: IBC patients with CTCs in PB had abnormalities in adaptive immunity that could potentially impact tumor cell dissemination and initiation of the metastatic cascade. PMID:27326253

  2. Research Progress on the Mechanism of the Influences of Traditional Chinese Medicine on Inflammation Immunity%中药影响炎症免疫反应的机制研究进展

    周松; 刘永刚; 张国祥; 李芳君

    2012-01-01

    The inflammation immunity is a defense response of the living tissue of vascular system to the damaging factors, a tissue injury caused by the damaging factors. The clinical pharmacological research of the inflammation immunity focuses on the function mechanism, which includes influencing the function of hypothalamus-pituitary-adrenal axis,inflammatory medium,nuclear factor,the generation of reactive oxygen species,apoptosis resulted from the cell function and the generation of neuroendocrine hormone,etc. For traditional Chinese medicine( TCM ). A lot of chemical medicines have serious adverse effects,while TCM has much less. Therefore, the mechanism of TCM influence on inflammation immunity has drawn extensive attention.%炎症免疫反应是血管系统的活体组织对损伤因子的防御反应,是由损伤因子引起的组织损伤.临床药理学对炎症免疫反应的研究集中于作用机制方面,而中药影响炎症免疫反应的机制包括影响下丘脑-垂体-肾上腺皮质轴的功能、炎性介质的作用、核因子的功能、活性氧的生成、细胞功能而导致凋亡以及神经内分泌激素的生成等.因许多化学药物在影响炎症免疫反应过程中存在严重不良反应,而中药的不良反应少,故中药影响炎症免疫反应的机制已受到广泛的关注.

  3. Immunity challenge.

    Davenport, R John

    2003-06-11

    As people get older, their immune systems falter. The elderly are more susceptible to infections than youngsters are, and hyperactive inflammatory responses appear to contribute to some age-associated illnesses, including Alzheimer's disease and atherosclerosis. Investigating the effect of aging on the immune system was once a scientific stepchild, but card-carrying immunologists are now tackling the problem head-on. Despite the immune system's complexity, researchers have started to make sense of how its components change with age. As the research progresses, scientists hope to bolster elderly people's response to infectious diseases and quiet the inflammation that can make aging a painful experience. PMID:12844525

  4. Trauma-induced heterotopic bone formation and the role of the immune system: A review.

    Kraft, Casey T; Agarwal, Shailesh; Ranganathan, Kavitha; Wong, Victor W; Loder, Shawn; Li, John; Delano, Matthew J; Levi, Benjamin

    2016-01-01

    Extremity trauma, spinal cord injuries, head injuries, and burn injuries place patients at high risk of pathologic extraskeletal bone formation. This heterotopic bone causes severe pain, deformities, and joint contractures. The immune system has been increasingly implicated in this debilitating condition. This review summarizes the various roles immune cells and inflammation play in the formation of ectopic bone and highlights potential areas of future investigation and treatment. Cell types in both the innate and adaptive immune system such as neutrophils, macrophages, mast cells, B cells, and T cells have all been implicated as having a role in ectopic bone formation through various mechanisms. Many of these cell types are promising areas of therapeutic investigation for potential treatment. The immune system has also been known to also influence osteoclastogenesis, which is heavily involved in ectopic bone formation. Chronic inflammation is also known to have an inhibitory role in the formation of ectopic bone, whereas acute inflammation is necessary for ectopic bone formation. PMID:26491794

  5. The therapeutic value of targeting inflammation in gastrointestinal cancers

    Sun, Beicheng; Karin, Michael

    2014-01-01

    Inflammation has been implicated in the initiation and progression of gastrointestinal (GI) cancers. Inflammation also plays important roles in subverting immune tolerance, escape from immune surveillance, and conferring resistance to chemotherapeutic agents. Targeting key regulators and mediators of inflammation represents an attractive strategy for GI cancer prevention and treatment. However, the targeting of inflammation in GI cancer is not straight-forward and sometimes inflammation may c...

  6. Retroperitoneal inflammation

    ... page: //medlineplus.gov/ency/article/001255.htm Retroperitoneal inflammation To use the sharing features on this page, please enable JavaScript. Retroperitoneal inflammation is swelling that occurs in the retroperitoneal space. ...

  7. Plasmacytoid Dendritic Cells Act as the Most Competent Cell Type in Linking Antiviral Innate and Adaptive Immune Responses

    Zheng Zhang; Fu-Sheng Wang

    2005-01-01

    Appropriate in vivo control of plasmacytoid dendritic cell (pDC) recruitment and activation is a fundamental requirement for defense against viral infection. During this process, a pivotal event that influences the outcome of viral infection is the production of high levels of type I interferon by pDCs. In particular, recent research findings showed that pDCs not only shape the nature of innate resistance, but are also responsible for the successful transition from innate to adaptive immunity for viral resistance. In addition, pDCs can differentiate into antigen presenting cells that may regulate tolerance to a given pathogen. Importantly, in a series of recent clinical studies,pDCs appeared to be defective in number and function in conditions of chronic viral diseases such as infected with HIV-1, HBV or HCV. pDC-associated clinical antiviral therapy is also emerging. This review describes research findings exanining the functional and antiviral properties of in vivo pDC plasticity.

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

    Silva Holtfreter

    2016-03-01

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

  9. iNKT-cell help to B cells: a cooperative job between innate and adaptive immune responses.

    Dellabona, Paolo; Abrignani, Sergio; Casorati, Giulia

    2014-08-01

    T-cell help to B lymphocytes is one of the most important events in adaptive immune responses in health and disease. It is generally delivered by cognate CD4(+) T follicular helper (T(FH)) cells via both cell-to-cell contacts and soluble mediators, and it is essential for both the clonal expansion of antibody (Ab)-secreting B cells and memory B-cell formation. CD1d-restricted invariant natural killer T (iNKT) cells are a subset of innate-like T lymphocytes that rapidly respond to stimulation with specific lipid antigens (Ags) that are derived from infectious pathogens or stressed host cells. Activated iNKT cells produce a wide range of cytokines and upregulate costimulatory molecules that can promote activation of dendritic cells (DCs), natural killer (NK) cells, and T cells. A decade ago, we discovered that iNKT cells can help B cells to proliferate and to produce IgG Abs in vitro and in vivo. This adjuvant-like function of Ag-activated iNKT cells provides a flexible set of helper mechanisms that expand the current paradigm of T-cell-B-cell interaction and highlights the potential of iNKT-cell targeting vaccine formulations. PMID:24782127

  10. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells

    Coccia, Margherita; Harrison, Oliver J.; Schiering, Chris; Asquith, Mark J.; Becher, Burkhard; Powrie, Fiona; Maloy, Kevin J.

    2012-01-01

    Although very high levels of interleukin (IL)-1β are present in the intestines of patients suffering from inflammatory bowel diseases (IBD), little is known about the contribution of IL-1β to intestinal pathology. Here, we used two complementary models of chronic intestinal inflammation to address the role of IL-1β in driving innate and adaptive pathology in the intestine. We show that IL-1β promotes innate immune pathology in Helicobacter hepaticus-triggered intestinal inflammation by augmen...

  11. Cold-Adapted Pandemic 2009 H1N1 Influenza Virus Live Vaccine Elicits Cross-Reactive Immune Responses against Seasonal and H5 Influenza A Viruses

    Jang, Yo Han; Byun, Young Ho; Lee, Yoon Jae; Lee, Yun Ha; Lee, Kwang-Hee; Seong, Baik Lin

    2012-01-01

    The rapid transmission of the pandemic 2009 H1N1 influenza virus (pH1N1) among humans has raised the concern of a potential emergence of reassortment between pH1N1 and highly pathogenic influenza strains, especially the avian H5N1 influenza virus. Here, we report that the cold-adapted pH1N1 live attenuated vaccine (CApH1N1) elicits cross-reactive immunity to seasonal and H5 influenza A viruses in the mouse model. Immunization with CApH1N1 induced both systemic and mucosal antibodies with broa...

  12. Lymphatic vessels regulate immune microenvironments in human and murine melanoma.

    Lund, Amanda W; Wagner, Marek; Fankhauser, Manuel; Steinskog, Eli S; Broggi, Maria A; Spranger, Stefani; Gajewski, Thomas F; Alitalo, Kari; Eikesdal, Hans P; Wiig, Helge; Swartz, Melody A

    2016-09-01

    Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment. PMID:27525437

  13. Adapt

    Bargatze, L. F.

    2015-12-01

    Active Data Archive Product Tracking (ADAPT) is a collection of software routines that permits one to generate XML metadata files to describe and register data products in support of the NASA Heliophysics Virtual Observatory VxO effort. ADAPT is also a philosophy. The ADAPT concept is to use any and all available metadata associated with scientific data to produce XML metadata descriptions in a consistent, uniform, and organized fashion to provide blanket access to the full complement of data stored on a targeted data server. In this poster, we present an application of ADAPT to describe all of the data products that are stored by using the Common Data File (CDF) format served out by the CDAWEB and SPDF data servers hosted at the NASA Goddard Space Flight Center. These data servers are the primary repositories for NASA Heliophysics data. For this purpose, the ADAPT routines have been used to generate data resource descriptions by using an XML schema named Space Physics Archive, Search, and Extract (SPASE). SPASE is the designated standard for documenting Heliophysics data products, as adopted by the Heliophysics Data and Model Consortium. The set of SPASE XML resource descriptions produced by ADAPT includes high-level descriptions of numerical data products, display data products, or catalogs and also includes low-level "Granule" descriptions. A SPASE Granule is effectively a universal access metadata resource; a Granule associates an individual data file (e.g. a CDF file) with a "parent" high-level data resource description, assigns a resource identifier to the file, and lists the corresponding assess URL(s). The CDAWEB and SPDF file systems were queried to provide the input required by the ADAPT software to create an initial set of SPASE metadata resource descriptions. Then, the CDAWEB and SPDF data repositories were queried subsequently on a nightly basis and the CDF file lists were checked for any changes such as the occurrence of new, modified, or deleted

  14. Intranasal Immunization with Influenza Virus-Like Particles Containing Membrane-Anchored Cholera Toxin B or Ricin Toxin B Enhances Adaptive Immune Responses and Protection against an Antigenically Distinct Virus

    Ji, Xianliang; Ren, Zhiguang; Xu, Na; Meng, Lingnan; Yu, Zhijun; Feng, Na; Sang, Xiaoyu; Li, Shengnan; Li, Yuanguo; Wang, Tiecheng; Zhao, Yongkun; Wang, Hualei; Zheng, Xuexing; Jin, Hongli; Li, Nan; Yang, Songtao; Cao, Jinshan; Liu, Wensen; Gao, Yuwei; Xia, Xianzhu

    2016-01-01

    Vaccination is the most effective means to prevent influenza virus infection, although current approaches are associated with suboptimal efficacy. Here, we generated virus-like particles (VLPs) composed of the hemagglutinin (HA), neuraminidase (NA) and matrix protein (M1) of A/Changchun/01/2009 (H1N1) with or without either membrane-anchored cholera toxin B (CTB) or ricin toxin B (RTB) as molecular adjuvants. The intranasal immunization of mice with VLPs containing membrane-anchored CTB or RTB elicited stronger humoral and cellular immune responses when compared to mice immunized with VLPs alone. Administration of VLPs containing CTB or RTB significantly enhanced virus-specific systemic and mucosal antibody responses, hemagglutination inhibiting antibody titers, virus neutralizing antibody titers, and the frequency of virus-specific IFN-γ and IL-4 secreting splenocytes. VLPs with and without CTB or RTB conferred complete protection against lethal challenge with a mouse-adapted homologous virus. When challenged with an antigenically distinct H1N1 virus, all mice immunized with VLPs containing CTB or RTB survived whereas mice immunized with VLPs alone showed only partial protection (80% survival). Our results suggest that membrane-anchored CTB and RTB possess strong adjuvant properties when incorporated into an intranasally-delivered influenza VLP vaccine. Chimeric influenza VLPs containing CTB or RTB may represent promising vaccine candidates for improved immunological protection against homologous and antigenically distinct influenza viruses. PMID:27110810

  15. Influence of Immune Responses in Gene/Stem Cell Therapies for Muscular Dystrophies

    Andrea Farini

    2014-01-01

    Full Text Available Muscular dystrophies (MDs are a heterogeneous group of diseases, caused by mutations in different components of sarcolemma, extracellular matrix, or enzymes. Inflammation and innate or adaptive immune response activation are prominent features of MDs. Various therapies under development are directed toward rescuing the dystrophic muscle damage using gene transfer or cell therapy. Here we discussed current knowledge about involvement of immune system responses to experimental therapies in MDs.

  16. IL-33-Responsive Lineage−CD25+CD44hi Lymphoid Cells Mediate Innate Type-2 Immunity and Allergic Inflammation in the Lungs1

    Bartemes, Kathleen R.; Iijima, Koji; Kobayashi, Takao; Gail M Kephart; McKenzie, Andrew N; Kita, Hirohito

    2011-01-01

    Innate immunity provides the first line of response to invading pathogens and a variety of environmental insults. Recent studies identified novel subsets of innate lymphoid cells that are capable of mediating immune responses in mucosal organs. Here we describe a subset of lymphoid cells that is involved in innate type-2 immunity in the lungs. Airway exposure of naïve BALB/c or C57BL mice to IL-33 results in a rapid (< 12 h) production of IL-5 and IL-13 and marked airway eosinophilia independ...

  17. Adaptive Immunity against Streptococcus pyogenes in Adults Involves Increased IFN-gamma and IgG3 Responses Compared with Children

    Mortensen, Rasmus; Nissen, Thomas Norrelykke; Blauenfeldt, Thomas;

    2015-01-01

    Each year, millions of people are infected with Streptococcus pyogenes, leading to an estimated 500,000 annual deaths worldwide. For unknown reasons, school-aged children have substantially higher infection rates than adults. The goal for this study was to provide, to our knowledge, the first...... detailed characterization of the human adaptive immune response against S. pyogenes in both children and adults. We report that all adults in our study, as well as most children, showed immunity against the two conserved group A streptococci (GAS) Ags, streptococcal C5a peptidase and immunogenic secreted...... significantly with IFN-γ, but not with IL-5, IL-13, IL-17, or TNF-α. Interestingly, children showed a similar pattern of Ag-specific cytokine release, but displayed significantly lower levels of IgG3 and IFN-γ compared with adults. Thus, human immune responses against S. pyogenes consist of a robust Th1...

  18. [Pathophysiology of inflammation].

    Sahlmann, C-O; Ströbel, P

    2016-02-15

    Inflammation results from activation of the immune system in response to a broad range of different stimuli. The immune system is a highly complex and evolutionary optimized defense system with cellular and humoral components. The course of an inflammatory response is influenced by the immune condition of the host, the virulence e. g. of an infectious agent, and the fine tuning of the local tissue reaction, which may be influenced by individual genetic factors. Immunity is a compromise between insufficient (immunodeficiency) or exaggerated (autoimmunity) immune reactions. The dynamic balance between these two extremes is achieved through stringent T- and B-cell selection in the bone marrow and thymus on the one hand and through "checkpoint control" in peripheral lymphatic tissues. Many tumors have ways to suppress local immune responses and to escape destruction through the immune system (one of the so-called "hallmarks of cancer"). In recent years, different approaches have successfully been able to reverse this local immunosuppression. First clinical trials using these strategies have shown highly promising results indicating that the therapeutic use of the immune system will be a very effective instrument in the arsenal of cancer treatment agents. PMID:26875429

  19. Crosstalk between innate and adaptive immune responses to infectious bronchitis virus after vaccination and challenge of chickens varying in serum mannose-binding lectin concentrations

    Juul-Madsen, Helle R.; Norup, Liselotte R.; Jørgensen, Poul Henrik;

    2011-01-01

    . Serum MBL levels also influenced IBV vaccine-induced changes in circulating T-cell populations. Moreover, addition of mannose to an IBV vaccine altered both vaccine-induced changes in circulating T-cell populations and IBV specific vaccine and infection-induced antibody responses in chickens with high...... serum MBL levels. These data demonstrate that MBL is involved in the regulation of the adaptive immune response to IBV....

  20. Immunity booster

    The immunity booster is, according to its patent description, microbiologically pure water with an D/(D+H) isotopic concentration of 100 ppm, with physical-chemical characteristics similar to those of distilled water. It is obtained by sterilization of a mixture of deuterium depleted water, with a 25 ppm isotopic concentration, with distilled water in a volume ratio of 4:6. Unlike natural immunity boosters (bacterial agents as Bacillus Chalmette-Guerin, Corynebacterium parvum; lipopolysaccharides; human immunoglobulin) or synthetical products (levamysol; isoprinosyne with immunostimulating action), which cause hypersensitivity and shocks, thrill, fever, sickness and the immunity complex disease, the water of 100 ppm D/(D + H) isotopic concentration is a toxicity free product. The testing for immune reaction of the immunity booster led to the following results: - an increase of cell action capacity in the first immunity shielding stage (macrophages), as evidenced by stimulation of a number of essential characterizing parameters, as well as of the phagocytosis capacity, bactericide capacity, and opsonic capacity of serum; - an increase of the number of leucocyte particularly of the granulocyte in peripheral blood, produced especially when medullar toxic agents like caryolysine are used; - it hinders the effect of lowering the number of erythrocytes in peripheral blood produced by experimentally induced chronic inflammation; - an increase of nonspecific immunity defence capacity against specific bacterial aggression of both Gram-positive bacteria (Streptococcus pneumoniae558) and of the Gram-negative ones (Klebsiella pneumoniae 507); - an increase of immunity - stimulating activity (proinflamatory), like that of levamisole as evidenced by the test of stimulation of experimentally induced inflammation by means of carrageenan. The following advantages of the immunity booster are stressed: - it is toxicity free and side effect free; - can be orally administrated as food

  1. Neural circuitry and immunity.

    Pavlov, Valentin A; Tracey, Kevin J

    2015-12-01

    Research during the last decade has significantly advanced our understanding of the molecular mechanisms at the interface between the nervous system and the immune system. Insight into bidirectional neuro-immune communication has characterized the nervous system as an important partner of the immune system in the regulation of inflammation. Neuronal pathways, including the vagus nerve-based inflammatory reflex, are physiological regulators of immune function and inflammation. In parallel, neuronal function is altered in conditions characterized by immune dysregulation and inflammation. Here, we review these regulatory mechanisms and describe the neural circuitry modulating immunity. Understanding these mechanisms reveals possibilities to use targeted neuromodulation as a therapeutic approach for inflammatory and autoimmune disorders. These findings and current clinical exploration of neuromodulation in the treatment of inflammatory diseases define the emerging field of Bioelectronic Medicine. PMID:26512000

  2. Monocyte Trafficking to the Brain with Stress and Inflammation: A Novel Axis of Immune-to-Brain Communication that Influences Mood and Behavior

    Wohleb, Eric S; McKim, Daniel B.; Sheridan, John F.; Godbout, Jonathan P.

    2015-01-01

    Psychological stressors cause physiological, immunological, and behavioral alterations in humans and rodents that can be maladaptive and negatively affect quality of life. Several lines of evidence indicate that psychological stress disrupts key functional interactions between the immune system and brain that ultimately affects mood and behavior. For example, activation of microglia, the resident innate immune cells of the brain, has been implicated as a key regulator of mood and behavior in ...

  3. Enforced expression of Gata3 in T cells and group 2 innate lymphoid cells increases susceptibility to allergic airway inflammation in mice

    A. Kleinjan (Alex); R.G.J. Klein Wolterink (Roel); Y. Levani (Yelvi); M.J.W. de Bruijn (Marjolein); H.C. Hoogsteden (Henk); M. van Nimwegen (Menno); R.W. Hendriks (Rudi)

    2014-01-01

    textabstractAirway inflammation in allergic asthma reflects a threshold response of the innate immune system, including group 2 innate lymphoid cells (ILC2), followed by an adaptive Th2 cell-mediated response. Transcription factor Gata3 is essential for differentiation of both Th2 cells and ILC2. We

  4. Splenectomy inhibits non-small cell lung cancer growth by modulating anti-tumor adaptive and innate immune response

    Levy, Liran; Mishalian, Inbal; Bayuch, Rachel; Zolotarov, Lida; Michaeli, Janna; Fridlender, Zvi G.

    2015-01-01

    It has been shown that inhibitors of the immune system reside in the spleen and inhibit the endogenous antitumor effects of the immune system. We hypothesized that splenectomy would inhibit the growth of relatively large non-small lung cancer (NSCLC) tumors by modulating the systemic inhibition of the immune system, and in particular Myeloid Derived Suppressor Cells (MDSC). The effect of splenectomy was evaluated in several murine lung cancer models. We found that splenectomy reduces tumor gr...

  5. Chronic Inflammation and γδ T Cells.

    Fay, Nathan S; Larson, Emily C; Jameson, Julie M

    2016-01-01

    The epithelial tissues of the skin, lungs, reproductive tract, and intestines are the largest physical barriers the body has to protect against infection. Epithelial tissues are woven with a matrix of immune cells programed to mobilize the host innate and adaptive immune responses. Included among these immune cells are gamma delta T lymphocytes (γδ T cells) that are unique in their T cell receptor usage, location, and functions in the body. Stress reception by γδ T cells as a result of traumatic epithelial injury, malignancy, and/or infection induces γδ T cell activation. Once activated, γδ T cells function to repair tissue, induce inflammation, recruit leukocytes, and lyse cells. Many of these functions are mediated via the production of cytokines and growth factors upon γδ T cell activation. Pathogenesis of many chronic inflammatory diseases involves γδ T cells; some of which are exacerbated by their presence, while others are improved. γδ T cells require a delicate balance between their need for acute inflammatory mediators to function normally and the detrimental impact imparted by chronic inflammation. This review will focus on the recent progress made in understanding how epithelial γδ T cells influence the pathogenesis of chronic inflammatory diseases and how a balance between acute and chronic inflammation impacts γδ T cell function. Future studies will be important to understand how this balance is achieved. PMID:27303404

  6. Chronic Inflammation and  T Cells

    Nathan S Fay

    2016-05-01

    Full Text Available The epithelial tissues of the skin, lungs, reproductive tract, and intestines are the largest physical barriers the body has to protect against infection. Epithelial tissues are woven with a matrix of immune cells programmed to mobilize the host innate and adaptive immune responses. Included among these immune cells are  T cells that are unique in their TCR usage, location, and functions in the body. Stress reception by  T cells as a result of traumatic epithelial injury, malignancy, and/or infection induces  T cell activation. Once activated,  T cells function to repair tissue, induce inflammation, recruit leukocytes, and lyse cells. Many of these functions are mediated via the production of cytokines and growth factors upon  T cell activation. Pathogenesis of many chronic inflammatory diseases involve  T cells; some of which are exacerbated by their presence, while others are improved.  T cells require a delicate balance between their need for acute inflammatory mediators to function normally and the detrimental impact imparted by chronic inflammation. This review will focus on the recent progress made in understanding how epithelial  T cells influence the pathogenesis of chronic inflammatory diseases and how a balance between acute and chronic inflammation impacts  T cell function. Future studies will be important to understand how this balance is achieved.

  7. Lung effector memory and activated CD4+ T cells display enhanced proliferation in SP-A-deficient mice during allergen-mediated inflammation

    Pastva, Amy M.; Mukherjee, Sambuddho; Giamberardino, Charles; Hsia, Bethany; Lo, Bernice; Sempowski, Gregory D; Wright, Jo Rae

    2011-01-01

    Although many studies show that pulmonary Surfactant Protein A (SP-A) functions in innate immunity, fewer studies have addressed its role in adaptive immunity and allergic hypersensitivity. We hypothesized that SP-A modulates the phenotype and prevalence of dendritic cells (DCs) and CD4+ T cells to inhibit Th2-associated inflammatory indices associated with allergen-induced inflammation. In an ovalbumin (OVA) model of allergic hypersensitivity, SP-A deficient (SP-A−/−) mice had greater eosino...

  8. Periostin in Allergic Inflammation

    Kenji Izuhara

    2014-01-01

    Full Text Available Periostin, an extracellular matrix protein belonging to the fasciclin family, has been shown to play a critical role in the process of remodeling during tissue/organ development or repair. Periostin functions as a matricellular protein in cell activation by binding to their receptors on cell surface, thereby exerting its biological activities. After we found that periostin is a downstream molecule of interleukin (IL-4 and IL-13, signature cytokines of type 2 immune responses, we showed that periostin is a component of subepithelial fibrosis in bronchial asthma, the first formal proof that periostin is involved in allergic inflammation. Subsequently, a great deal of evidence has accumulated demonstrating the significance of periostin in allergic inflammation. It is of note that in skin tissues, periostin is critical for amplification and persistence of allergic inflammation by communicating between fibroblasts and keratinocytes. Furthermore, periostin has been applied to development of novel diagnostics or therapeutic agents for allergic diseases. Serum periostin can reflect local production of periostin in inflamed lesions induced by Th2-type immune responses and also can predict the efficacy of Th2 antagonists against bronchial asthma. Blocking the interaction between periostin and its receptor, αv integrin, or down-regulating the periostin expression shows improvement of periostin-induced inflammation in mouse models or in in vitro systems. It is hoped that diagnostics or therapeutic agents targeting periostin will be of practical use in the near future.

  9. NOX2-dependent regulation of inflammation.

    Singel, Kelly L; Segal, Brahm H

    2016-04-01

    NADPH oxidase (NOX) isoforms together have multiple functions that are important for normal physiology and have been implicated in the pathogenesis of a broad range of diseases, including atherosclerosis, cancer and neurodegenerative diseases. The phagocyte NADPH oxidase (NOX2) is critical for antimicrobial host defence. Chronic granulomatous disease (CGD) is an inherited disorder of NOX2 characterized by severe life-threatening bacterial and fungal infections and by excessive inflammation, including Crohn's-like inflammatory bowel disease (IBD). NOX2 defends against microbes through the direct antimicrobial activity of reactive oxidants and through activation of granular proteases and generation of neutrophil extracellular traps (NETs). NETosis involves the breakdown of cell membranes and extracellular release of chromatin and neutrophil granular constituents that target extracellular pathogens. Although the immediate effects of oxidant generation and NETosis are predicted to be injurious, NOX2, in several contexts, limits inflammation and injury by modulation of key signalling pathways that affect neutrophil accumulation and clearance. NOX2 also plays a role in antigen presentation and regulation of adaptive immunity. Specific NOX2-activated pathways such as nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional factor that induces antioxidative and cytoprotective responses, may be important therapeutic targets for CGD and, more broadly, diseases associated with excessive inflammation and injury. PMID:26888560

  10. Gene expression profiling of Gram-negative bacteria-induced inflammation in human whole blood: The role of complement and CD14-mediated innate immune response

    Lau, Corinna; Olstad, Ole Kristoffer; Holden, Marit; Nygård, Ståle; Fure, Hilde; Lappegård, Knut Tore; Brekke, Ole-Lars; Espevik, Terje; Hovig, Eivind; Mollnes, Tom Eirik

    2015-01-01

    Non-sterile pathogen-induced sepsis and sterile inflammation like in trauma or ischemia–reperfusion injury may both coincide with the life threatening systemic inflammatory response syndrome and multi-organ failure. Consequently, there is an urgent need for specific biomarkers in order to distinguish sepsis from sterile conditions. The overall aim of this study was to uncover putative sepsis biomarkers and biomarker pathways, as well as to test the efficacy of combined inhibition of innate im...

  11. Sterile inflammation – do innate lymphoid cell subsets play a role?

    Shane E Russell; Walsh, Patrick T.

    2012-01-01

    The recent identification of several novel innate lymphoid cell (iLC) subsets has increased our understanding of the mechanisms which link the innate and adaptive immune systems. While the contribution of these subsets toward the pathogenesis of human disease remains largely to be determined, it seems likely that they will play a particularly important role in sterile inflammatory settings where the innate response is seen as a critical mediator of inflammation. Several recent studies have hi...

  12. Sterile Inflammation-Do innate lymphoid cell subsets play a role?

    Shane E Russell; Walsh, Patrick T.

    2012-01-01

    The recent identification of several novel innate lymphoid cell subsets (iLCs) has increased our understanding of the mechanisms which link the innate and adaptive immune systems. While the contribution of these subsets towards the pathogenesis of human disease remains largely to be determined, it seems likely that they will play a particularly important role in sterile inflammatory settings where the innate response is seen as a critical mediator of inflammation. Several recent studies have ...

  13. The Role of Non-specific and Specific Immune Systems in Poultry against Newcastle Disease

    Dyah Ayu Hewajuli

    2015-09-01

    Full Text Available Newcastle disease (ND is caused by avian paramyxovirus-1 which belong to Avulavirus genus and Paramyxoviridae family. The birds have abnormalities in humoral (bursa fabricius and cellular (thymus and spleen lymphoid organs. Lesions decrease the immune system. Immune system consists of non-specific and specific immune systems. The main components of non-specific immunity are physical and chemical barrier (feather and skin or mucosa, phagocytic cells (macrophages and natural killer, protein complement and the mediator of inflammation and cytokines. Interferons (IFNs belong to a group of cytokines that play a major role in the nonspecific or innate (natural immunity. The virulent ND virus encodes protein of V gene can be suppressed IFN type I. This leads to non-specific immune system fail to respond to the virulent strains resulting in severe pathogenicity. The defense mechanism of the host is replaced by specific immunity (adaptive immunity when natural immunity fails to overcome the infection. The specific immune system consists of humoral mediated immunity (HMI and cell-mediated immunity (CMI. The cells of immune system that react specifically with the antigen are B lymphocytes producing the antibodies, T lymphocytes that regulate the synthesis of antibodies and T cells as effector or the direct cytotoxic cells. Both non-specific and specific immunities are complementary against the invasion of ND virus in the birds. The objective of this article is to discuss the role of non specific and specific immune system in ND.

  14. The impact of ruxolitinib treatment on inflammation-mediated comorbidities in myelofibrosis and related neoplasms

    Bjørn, Mads Emil; Hasselbalch, Hans Carl

    2015-01-01

    The inflammation-mediated comorbidities in myelofibrosis (MF) and related neoplasms (MPNs) likely reflect the concurrent immune deregulation and systemic inflammatory nature of the MPNs, emphasizing the link between chronic systemic inflammation, immune deregulation, and the malignant clone. JAK1...

  15. Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells.

    Göbel, Kerstin; Pankratz, Susann; Asaridou, Chloi-Magdalini; Herrmann, Alexander M; Bittner, Stefan; Merker, Monika; Ruck, Tobias; Glumm, Sarah; Langhauser, Friederike; Kraft, Peter; Krug, Thorsten F; Breuer, Johanna; Herold, Martin; Gross, Catharina C; Beckmann, Denise; Korb-Pap, Adelheid; Schuhmann, Michael K; Kuerten, Stefanie; Mitroulis, Ioannis; Ruppert, Clemens; Nolte, Marc W; Panousis, Con; Klotz, Luisa; Kehrel, Beate; Korn, Thomas; Langer, Harald F; Pap, Thomas; Nieswandt, Bernhard; Wiendl, Heinz; Chavakis, Triantafyllos; Kleinschnitz, Christoph; Meuth, Sven G

    2016-01-01

    Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders. PMID:27188843

  16. Imaging Immunity in Lymph Nodes: Past, Present and Future.

    Butler, James; Sawtell, Amy; Jarrett, Simon; Cosgrove, Jason; Leigh, Roger; Timmis, Jon; Coles, Mark

    2016-01-01

    Immune responses occur as a result of stochastic interactions between a plethora of different cell types and molecules that regulate the migration and function of innate and adaptive immune cells to drive protection from pathogen infection. The trafficking of immune cells into peripheral tissues during inflammation and then subsequent migration to draining lymphoid tissues has been quantitated using radiolabelled immune cells over 40 years ago. However, how these processes lead to efficient immune responses was unclear. Advances in physics (multi-photon), chemistry (probes) and biology (animal models) have provided immunologists with specialized tools to quantify the molecular and cellular mechanisms driving immune function in lymphoid tissues through directly visualising cellular behaviours in 3-dimensions over time. Through the temporal and spatial resolution of multi-photon confocal microscopy immunologists have developed new insights into normal immune homeostasis, host responses to pathogens, anti-tumour immune responses and processes driving development of autoimmune pathologies, by the quantification of the interactions and cellular migration involved in adaptive immune responses. Advances in deep tissue imaging, including new fluorescent proteins, increased resolution, speed of image acquisition, sensitivity, number of signals and improved data analysis techniques have provided unprecedented capacity to quantify immune responses at the single cell level. This quantitative information has facilitated development of high-fidelity mathematical and computational models of immune function. Together this approach is providing new mechanistic understanding of immune responses and new insights into how immune modulators work. Advances in biophysics have therefore revolutionised our understanding of immune function, directly impacting on the development of next generation immunotherapies and vaccines, and is providing the quantitative basis for emerging technology

  17. Multi-metal contamination with uranium trend impact on aquatic environment and consequences for fish immune system and adaptive responses

    Le Guernic, A.; Gagnaire, B. [IRSN/PRP-ENV/SERIS/LECO (France); Sanchez, W. [Institut national de l' environnement industriel et des risques - INERIS (France); Betoulle, S. [Champagne Ardenne University (France)

    2014-07-01

    Human activities have conducted to an increase of concentrations of various metals in aquatic ecosystems, including uranium. Its extraction and use have been rapidly magnified because of its role in the nuclear fuel cycle. These activities have led to high concentrations of uranium in the aquatic environment and thus a potential risk to exposed organisms, including fish. Consequences can be observed through metabolic and physiological responses, called biomarkers. Some biomarkers are interesting in order to evaluate the effects of metal contamination, among other immunotoxicity markers, antioxidant defenses and genotoxicity. The aims of this study are: i) to investigate the effects of a multi-metal contamination on a fish, the three-spined stickleback, Gasterosteus aculeatus, and ii) to observe the adaptive capacity of fish due to a combination of stress (chemical stress and biological stress). To meet the first objective, six water bodies (ponds and lakes) located in two departments (Cantal and Haute-Vienne, France) were chosen according to their proximity to old uranium mines and to their levels of metal contamination related to chemical processes appeared during extraction. 240 three-spined sticklebacks were caged for 28 days in the six selected sites. A battery of biomarkers was measured in fish sampled after 14 and 28 of caging. The results for the Haute-Vienne department showed that caged fish in the pond with the highest uranium concentration (20 μg.L{sup -1}) presented the most DNA damage after 14 days of caging. Leukocyte phagocytosis (marker of immunotoxicity) of caged fish in this pond was lower at 14 days and greater at 28 days compared to other ponds without uranium. The multi-metal contamination negatively affected other parameters such as the condition index, oxidative activity, viability of lysosomal membrane and leukocytes distribution. In order to study the response of fish to a combined stress (chemical + biological) (objective ii), a second

  18. Multi-metal contamination with uranium trend impact on aquatic environment and consequences for fish immune system and adaptive responses

    Human activities have conducted to an increase of concentrations of various metals in aquatic ecosystems, including uranium. Its extraction and use have been rapidly magnified because of its role in the nuclear fuel cycle. These activities have led to high concentrations of uranium in the aquatic environment and thus a potential risk to exposed organisms, including fish. Consequences can be observed through metabolic and physiological responses, called biomarkers. Some biomarkers are interesting in order to evaluate the effects of metal contamination, among other immunotoxicity markers, antioxidant defenses and genotoxicity. The aims of this study are: i) to investigate the effects of a multi-metal contamination on a fish, the three-spined stickleback, Gasterosteus aculeatus, and ii) to observe the adaptive capacity of fish due to a combination of stress (chemical stress and biological stress). To meet the first objective, six water bodies (ponds and lakes) located in two departments (Cantal and Haute-Vienne, France) were chosen according to their proximity to old uranium mines and to their levels of metal contamination related to chemical processes appeared during extraction. 240 three-spined sticklebacks were caged for 28 days in the six selected sites. A battery of biomarkers was measured in fish sampled after 14 and 28 of caging. The results for the Haute-Vienne department showed that caged fish in the pond with the highest uranium concentration (20 μg.L-1) presented the most DNA damage after 14 days of caging. Leukocyte phagocytosis (marker of immunotoxicity) of caged fish in this pond was lower at 14 days and greater at 28 days compared to other ponds without uranium. The multi-metal contamination negatively affected other parameters such as the condition index, oxidative activity, viability of lysosomal membrane and leukocytes distribution. In order to study the response of fish to a combined stress (chemical + biological) (objective ii), a second

  19. Cold-adapted influenza and recombinant adenovirus vaccines induce cross-protective immunity against pH1N1 challenge in mice.

    Mark R Soboleski

    Full Text Available BACKGROUND: The rapid spread of the 2009 H1N1 pandemic influenza virus (pH1N1 highlighted problems associated with relying on strain-matched vaccines. A lengthy process of strain identification, manufacture, and testing is required for current strain-matched vaccines and delays vaccine availability. Vaccines inducing immunity to conserved viral proteins could be manufactured and tested in advance and provide cross-protection against novel influenza viruses until strain-matched vaccines became available. Here we test two prototype vaccines for cross-protection against the recent pandemic virus. METHODOLOGY/PRINCIPAL FINDINGS: BALB/c and C57BL/6 mice were intranasally immunized with a single dose of cold-adapted (ca influenza viruses from 1977 or recombinant adenoviruses (rAd expressing 1934 nucleoprotein (NP and consensus matrix 2 (M2 (NP+M2-rAd. Antibodies against the M2 ectodomain (M2e were seen in NP+M2-rAd immunized BALB/c but not C57BL/6 mice, and cross-reacted with pH1N1 M2e. The ca-immunized mice did not develop antibodies against M2e. Despite sequence differences between vaccine and challenge virus NP and M2e epitopes, extensive cross-reactivity of lung T cells with pH1N1 peptides was detected following immunization. Both ca and NP+M2-rAd immunization protected BALB/c and C57BL/6 mice against challenge with a mouse-adapted pH1N1 virus. CONCLUSION/SIGNIFICANCE: Cross-protective vaccines such as NP+M2-rAd and ca virus are effective against pH1N1 challenge within 3 weeks of immunization. Protection was not dependent on recognition of the highly variable external viral proteins and could be achieved with a single vaccine dose. The rAd vaccine was superior to the ca vaccine by certain measures, justifying continued investigation of this experimental vaccine even though ca vaccine is already available. This study highlights the potential for cross-protective vaccines as a public health option early in an influenza pandemic.

  20. Gene expression profiling of Gram-negative bacteria-induced inflammation in human whole blood: The role of complement and CD14-mediated innate immune response

    Corinna Lau; Ole Kristoffer Olstad; Marit Holden; Ståle Nygård; Hilde Fure; Knut Tore Lappegård; Ole-Lars Brekke; Terje Espevik; Eivind Hovig; Tom Eirik Mollnes

    2016-01-01

    This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Published version also available at http://dx.doi.org/10.1016/j.gdata.2015.05.019 Non-sterile pathogen-induced sepsis and sterile inflammation like in trauma or ischemia–reperfusion injury may both coincide with the life threatening systemic inflammatory response syndrome and multi-organ failure. Consequently, there is an urgent need for specific biomarkers in order to...

  1. Innate immunity in inflammatory bowel disease

    2007-01-01

    The human intestinal tract is home to an enormous bacterial flora. The host defense against microorganisms can be divided into innate and adaptive immunity. The former is the most immediate line of response to immunologic challenges presented by bacteria, viruses, and fungi. The mucosal immune system has evolved to balance the need to respond to pathogens while co-existing with commensal bacteria and food antigens. In inflammatory bowel disease (IBD), this hyporesponsiveness or tolerance breaks-down and inflammation supervenes driven by the intestinal microbial flora. Bacteria contain compounds and are recognized by a variety of receptors, including Toll-like receptors (TLRs) and NODs (a family of intracellular bacterial sensors) and are potent stimuli of innate immune responses. Several mutations in these receptors have been associated with development of IBD.

  2. Feeding Lactobacillus paracasei ssp. paracasei strain F19 to infants during weaning : effects on adaptive immunity and gut microbial function

    West, Christina

    2008-01-01

    Introduction: Gut microbial composition has been associated with immune-mediated diseases. Breastfeeding yields a microbiota rich in bifidobacteria and promotes colonization by lactobacilli. Bifidobacteria and lactobacilli are considered health-promoting and are used as probiotics, i.e. live microbial food supplements which when ingested in adequate amounts confer a beneficial effect on the host. During weaning the developing gut immune system is exposed to an increasing variety of antigens f...

  3. Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2.

    Zhu, Eric F; Gai, Shuning A; Opel, Cary F; Kwan, Byron H; Surana, Rishi; Mihm, Martin C; Kauke, Monique J; Moynihan, Kelly D; Angelini, Alessandro; Williams, Robert T; Stephan, Matthias T; Kim, Jacob S; Yaffe, Michael B; Irvine, Darrell J; Weiner, Louis M; Dranoff, Glenn; Wittrup, K Dane

    2015-04-13

    Cancer immunotherapies under development have generally focused on either stimulating T cell immunity or driving antibody-directed effector functions of the innate immune system such as antibody-dependent cell-mediated cytotoxicity (ADCC). We find that a combination of an anti-tumor antigen antibody and an untargeted IL-2 fusion protein with delayed systemic clearance induces significant tumor control in aggressive isogenic tumor models via a concerted innate and adaptive response involving neutrophils, NK cells, macrophages, and CD8(+) T cells. This combination therapy induces an intratumoral "cytokine storm" and extensive lymphocyte infiltration. Adoptive transfer of anti-tumor T cells together with this combination therapy leads to robust cures of established tumors and development of immunological memory. PMID:25873172

  4. Sublethal red tide toxin exposure in free-ranging manatees (Trichechus manatus) affects the immune system through reduced lymphocyte proliferation responses, inflammation, and oxidative stress

    Highlights: • Sublethal brevetoxin exposure affects manatee immune function. • Plasma brevetoxin levels correlate with oxidative stress in rescued manatees. • Brevetoxin exposure affects lymphocyte proliferation in rescued manatees. • Plasma brevetoxin concentrations ranged from 0 to 19 ng PbTx-3 eq/mL. - Abstract: The health of many Florida manatees (Trichechus manatus latirostris) is adversely affected by exposure to blooms of the toxic dinoflagellate, Karenia brevis. K. brevis blooms are common in manatee habitats of Florida’s southwestern coast and produce a group of cyclic polyether toxins collectively referred to as red tide toxins, or brevetoxins. Although a large number of manatees exposed to significant levels of red tide toxins die, several manatees are rescued from sublethal exposure and are successfully treated and returned to the wild. Sublethal brevetoxin exposure may potentially impact the manatee immune system. Lymphocyte proliferative responses and a suite of immune function parameters in the plasma were used to evaluate effects of brevetoxin exposure on health of manatees rescued from natural exposure to red tide toxins in their habitat. Blood samples were collected from rescued manatees at Lowry Park Zoo in Tampa, FL and from healthy, unexposed manatees in Crystal River, FL. Peripheral blood leukocytes (PBL) isolated from whole blood were stimulated with T-cell mitogens, ConA and PHA. A suite of plasma parameters, including plasma protein electrophoresis profiles, lysozyme activity, superoxide dismutase (SOD) activity, and reactive oxygen/nitrogen (ROS/RNS) species, was also used to assess manatee health. Significant decreases (p < 0.05) in lymphocyte proliferation were observed in ConA and PHA stimulated lymphocytes from rescued animals compared to non-exposed animals. Significant correlations were observed between oxidative stress markers (SOD, ROS/RNS) and plasma brevetoxin concentrations. Sublethal exposure to brevetoxins in the

  5. Immunization with Pneumococcal Polysaccharide Serotype 3 and Lipopolysaccharide Modulates Lung and Liver Inflammation during a Virulent Streptococcus pneumoniae Infection in Mice

    Restori, Katherine H.; Kennett, Mary J.; Ross, A. Catharine

    2013-01-01

    Vaccination reduces morbidity and mortality from pneumonia, but its effect on the tissue-level response to infection is still poorly understood. We evaluated pneumonia disease progression, acute-phase response, and lung gene expression profiles in mice inoculated intranasally with virulent Gram-positive Streptococcus pneumoniae serotype 3 (ST 3) with and without prior immunization with pneumococcal polysaccharide ST 3 (PPS3) or after coimmunization with PPS3 and a low dose of lipopolysacchari...

  6. Sublethal red tide toxin exposure in free-ranging manatees (Trichechus manatus) affects the immune system through reduced lymphocyte proliferation responses, inflammation, and oxidative stress

    Walsh, Catherine J., E-mail: cjwalsh@mote.org [Marine Immunology Program, Mote Marine Laboratory, 1600 Ken Thompson Parkway, Sarasota, FL 34236 (United States); Butawan, Matthew, E-mail: mattbutawan@outlook.com [Marine Immunology Program, Mote Marine Laboratory, 1600 Ken Thompson Parkway, Sarasota, FL 34236 (United States); Yordy, Jennifer, E-mail: jennifer.e.balmer@gmail.com [Marine Immunology Program, Mote Marine Laboratory, 1600 Ken Thompson Parkway, Sarasota, FL 34236 (United States); Ball, Ray, E-mail: Ray.Ball@lowryparkzoo.com [Lowry Park Zoo, 1101 W Sligh Ave, Tampa, FL 33604 (United States); Flewelling, Leanne, E-mail: Leanne.Flewelling@MyFWC.com [Fish and Wildlife Research Institute, Florida Fish and Wildlife Conservation Commission, 100 8th Ave SE, St. Petersburg, FL 33701 (United States); Wit, Martine de, E-mail: Martine.deWit@MyFWC.com [Fish and Wildlife Research Institute, Florida Fish and Wildlife Conservation Commission, 100 8th Ave SE, St. Petersburg, FL 33701 (United States); Bonde, Robert K., E-mail: rbonde@usgs.gov [U.S. Geological Survey, Sirenia Project, 7920 NE 71st Street, Gainesville, FL 32653 (United States)

    2015-04-15

    Highlights: • Sublethal brevetoxin exposure affects manatee immune function. • Plasma brevetoxin levels correlate with oxidative stress in rescued manatees. • Brevetoxin exposure affects lymphocyte proliferation in rescued manatees. • Plasma brevetoxin concentrations ranged from 0 to 19 ng PbTx-3 eq/mL. - Abstract: The health of many Florida manatees (Trichechus manatus latirostris) is adversely affected by exposure to blooms of the toxic dinoflagellate, Karenia brevis. K. brevis blooms are common in manatee habitats of Florida’s southwestern coast and produce a group of cyclic polyether toxins collectively referred to as red tide toxins, or brevetoxins. Although a large number of manatees exposed to significant levels of red tide toxins die, several manatees are rescued from sublethal exposure and are successfully treated and returned to the wild. Sublethal brevetoxin exposure may potentially impact the manatee immune system. Lymphocyte proliferative responses and a suite of immune function parameters in the plasma were used to evaluate effects of brevetoxin exposure on health of manatees rescued from natural exposure to red tide toxins in their habitat. Blood samples were collected from rescued manatees at Lowry Park Zoo in Tampa, FL and from healthy, unexposed manatees in Crystal River, FL. Peripheral blood leukocytes (PBL) isolated from whole blood were stimulated with T-cell mitogens, ConA and PHA. A suite of plasma parameters, including plasma protein electrophoresis profiles, lysozyme activity, superoxide dismutase (SOD) activity, and reactive oxygen/nitrogen (ROS/RNS) species, was also used to assess manatee health. Significant decreases (p < 0.05) in lymphocyte proliferation were observed in ConA and PHA stimulated lymphocytes from rescued animals compared to non-exposed animals. Significant correlations were observed between oxidative stress markers (SOD, ROS/RNS) and plasma brevetoxin concentrations. Sublethal exposure to brevetoxins in the

  7. Adjuvant effects of invariant NKT cell ligand potentiates the innate and adaptive immunity to an inactivated H1N1 swine influenza virus vaccine in pigs.

    Dwivedi, Varun; Manickam, Cordelia; Dhakal, Santosh; Binjawadagi, Basavaraj; Ouyang, Kang; Hiremath, Jagadish; Khatri, Mahesh; Hague, Jacquelyn Gervay; Lee, Chang Won; Renukaradhya, Gourapura J

    2016-04-15

    Pigs are considered as the source of some of the emerging human flu viruses. Inactivated swine influenza virus (SwIV) vaccine has been in use in the US swine herds, but it failed to control the flu outbreaks. The main reason has been attributed to lack of induction of strong local mucosal immunity in the respiratory tract. Invariant natural killer T (iNKT) cell is a unique T cell subset, and activation of iNKT cell using its ligand α-Galactosylceramide (α-GalCer) has been shown to potentiate the cross-protective immunity to inactivated influenza virus vaccine candidates in mice. Recently, we discovered iNKT cell in pig and demonstrated its activation using α-GalCer. In this study, we evaluated the efficacy of an inactivated H1N1 SwIV coadministered with α-GalCer intranasally against a homologous viral challenge. Our results demonstrated the potent adjuvant effects of α-GalCer in potentiating both innate and adaptive immune responses to SwIV Ags in the lungs of pigs, which resulted in reduction in the lung viral load by 3 logs compared to without adjuvant. Immunologically, in the lungs of pigs vaccinated with α-GalCer an increased virus specific IgA response, IFN-α secretion and NK cell-cytotoxicity was observed. In addition, iNKT cell-stimulation enhanced the secretion of Th1 cytokines (IFN-γ and IL-12) and reduced the production of immunosuppressive cytokines (IL-10 and TGF-β) in the lungs of pigs⋅ In conclusion, we demonstrated for the first time iNKT cell adjuvant effects in pigs to SwIV Ags through augmenting the innate and adaptive immune responses in the respiratory tract. PMID:27016770

  8. Monocyte Trafficking to the Brain with Stress and Inflammation: A Novel Axis of Immune-to-Brain Communication that Influences Mood and Behavior

    Eric S Wohleb

    2015-01-01

    Full Text Available Psychological stressors cause physiological, immunological, and behavioral alterations in humans and rodents that can be maladaptive and negatively affect quality of life. Several lines of evidence indicate that psychological stress disrupts key functional interactions between the immune system and brain that ultimately affects mood and behavior. For example, activation of microglia, the resident innate immune cells of the brain, has been implicated as a key regulator of mood and behavior in the context of prolonged exposure to psychological stress. Emerging evidence implicates a novel neuroimmune circuit involving microglia activation and sympathetic outflow to the peripheral immune system that further reinforces stress-related behaviors by facilitating the recruitment of inflammatory monocytes to the brain. Evidence from various rodent models, including repeated social defeat (RSD, revealed that trafficking of monocytes to the brain promoted the establishment of anxiety-like behaviors following prolonged stress exposure. In addition, new evidence implicates monocyte trafficking from the spleen to the brain as key regulator of recurring anxiety following exposure to prolonged stress. The purpose of this review is to discuss mechanisms that cause stress-induced monocyte re-distribution in the brain and how dynamic interactions between microglia, endothelial cells, and brain macrophages lead to maladaptive behavioral responses.

  9. Direct and Indirect Role of Toll-Like Receptors in T Cell Mediated Immunity

    DamoXu; HaiyingLiu; MousaKomai-Koma

    2004-01-01

    Toll-like receptors (TLR) are pathogen-associated molecular patterns (PAMPs) recognition receptors that play an important role in protective immunity against infection and inflammation. They act as central integrators of a wide variety of signals, responding to diverse agonists of microbial products. Stimulation of Toll-like receptors by microbial products leads to signaling pathways that activate not only innate, but also adaptive immunity by APC dependent or independent mechanisms. Recent evidence revealed that TLR signals played a determining role in the skewing of naive T cells towards either Thl or Th2 responses. Activation of Toll-like receptors also directly or indirectly influences regulatory T cell functions. Therefore, TLRs are required in both immune activation and immune regulation. Study of TLRs has significantly enhanced our understanding of innate and adaptive immune responses and provides novel therapeutic approaches against infectious and inflammatory diseases. Cellular & Molecular Immunology.

  10. Direct and Indirect Role of Toll-Like Receptors in T Cell Mediated Immunity

    Damo Xu; Haiying Liu; Mousa Komai-Koma

    2004-01-01

    Toll-like receptors (TLR) are pathogen-associated molecular patterns (PAMPs) recognition receptors that play an important role in protective immunity against infection and inflammation. They act as central integrators of a wide variety of signals, responding to diverse agonists of microbial products. Stimulation of Toll-like receptors by microbial products leads to signaling pathways that activate not only innate, but also adaptive immunity by APC dependent or independent mechanisms. Recent evidence revealed that TLR signals played a determining role in the skewing of na(i)ve T cells towards either Th1 or Th2 responses. Activation of Toll-like receptors also directly or indirectly influences regulatory T cell functions. Therefore, TLRs are required in both immune activation and immune regulation. Study of TLRs has significantly enhanced our understanding of innate and adaptive immune responses and provides novel therapeutic approaches against infectious and inflammatory diseases.

  11. Innate Response to Human Cancer Cells with or without IL-2 Receptor Common γ-Chain Function in NOD Background Mice Lacking Adaptive Immunity.

    Nishime, Chiyoko; Kawai, Kenji; Yamamoto, Takehiro; Katano, Ikumi; Monnai, Makoto; Goda, Nobuhito; Mizushima, Tomoko; Suemizu, Hiroshi; Nakamura, Masato; Murata, Mitsuru; Suematsu, Makoto; Wakui, Masatoshi

    2015-08-15

    Immunodeficient hosts exhibit high acceptance of xenogeneic or neoplastic cells mainly due to lack of adaptive immunity, although it still remains to be elucidated how innate response affects the engraftment. IL-2R common γ-chain (IL-2Rγc) signaling is required for development of NK cells and a subset of dendritic cells producing IFN-γ. To better understand innate response in the absence of adaptive immunity, we examined amounts of metastatic foci in the livers after intrasplenic transfer of human colon cancer HCT116 cells into NOD/SCID versus NOD/SCID/IL-2Rγc (null) (NOG) hosts. The intravital microscopic imaging of livers in the hosts depleted of NK cells and/or macrophages revealed that IL-2Rγc function critically contributes to elimination of cancer cells without the need for NK cells and macrophages. In the absence of IL-2Rγc, macrophages play a role in the defense against tumors despite the NOD Sirpa allele, which allows human CD47 to bind to the encoded signal regulatory protein α to inhibit macrophage phagocytosis of human cells. Analogous experiments using human pancreas cancer MIA PaCa-2 cells provided findings roughly similar to those from the experiments using HCT116 cells except for lack of suppression of metastases by macrophages in NOG hosts. Administration of mouse IFN-γ to NOG hosts appeared to partially compensate lack of IL-2Rγc-dependent elimination of transferred HCT116 cells. These results provide insights into the nature of innate response in the absence of adaptive immunity, aiding in developing tumor xenograft models in experimental oncology. PMID:26170385

  12. Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy – ACTG A5286

    Tenorio, Allan R.; Chan, Ellen S.; Bosch, Ronald J.; Macatangay, Bernard J. C.; Read, Sarah W.; Yesmin, Suria; Taiwo, Babafemi; Margolis, David M.; Jacobson, Jeffrey M.; Landay, Alan L.; Wilson, Cara C.; Mellors, John W.; Keshavarzian, Ali; Rodriguez, Benigno; Aziz, Mariam; Presti, Rachel; Deeks, Steven; Ebiasah, Ruth; Myers, Laurie; Borowski, LuAnn; Plants, Jill; Palm, David A.; Weibel, Derek; Putnam, Beverly; Lindsey, Elizabeth; Player, Amy; Albrecht, Mary; Kershaw, Andrea; Sax, Paul; Keenan, Cheryl; Walton, Patricia; Baum, Jane; Stroberg, Todd; Hughes, Valery; Coster, Laura; Kumar, Princy N.; Yin, Michael T.; Noel-Connor, Jolene; Tebas, Pablo; Thomas, Aleshia; Davis, Charles E.; Redfield, Robert R.; Sbrolla, Amy; Flynn, Teri; Davis, Traci; Whitely, Kim; Singh, Baljinder; Swaminathan, Shobha; McGregor, Donna; Palella, Frank; Aberg, Judith; Cavanagh, Karen; Santana Bagur, Jorge L.; Flores, Olga Méndez; Fritsche, Janice; Sha, Beverly; Slamowitz, Debbie; Valle, Sandra; Tashima, Karen; Patterson, Helen; Harber, Heather; Para, Michael; Eaton, Molly; Maddox, Dale; Currier, Judith; Cajahuaringa, Vanessa; Luetkemeyer, Annie; Dwyer, Jay; Fichtenbaum, Carl J.; Saemann, Michelle; Ray, Graham; Campbell, Thomas; Fischl, Margaret A.; Bolivar, Hector; Oakes, Jonathan; Chicurel-Bayard, Miriam; Tripoli, Christine; Weinman, D. Renee; Adams, Mary; Hurley, Christine; Dunaway, Shelia; Storey, Sheryl; Klebert, Michael; Royal, Michael

    2015-01-01

    Background. Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART). Methods. HIV-positive adults receiving ART for ≥96 weeks with undetectable viremia for ≥48 weeks and CD4+ T-cell counts <350 cells/mm3 were randomized 2:1 to rifaximin versus no study treatment for 4 weeks. T-cell activation, LPS, and soluble CD14 were measured at baseline and at weeks 2, 4, and 8. Wilcoxon rank sum tests compared changes between arms. Results. Compared with no study treatment (n = 22), rifaximin (n = 43) use was associated with a significant difference between study arms in the change from baseline to week 4 for CD8+T-cell activation (median change, 0.0% with rifaximin vs +0.6% with no treatment; P = .03). This difference was driven by an increase in the no-study-treatment arm because there was no significant change within the rifaximin arm. Similarly, although there were significant differences between study arms in change from baseline to week 2 for LPS and soluble CD14, there were no significant changes within the rifaximin arm. Conclusions. In immune nonresponders to ART, rifaximin minimally affected microbial translocation and CD8+T-cell activation. Trial registration number. NCT01466595. PMID:25214516

  13. Beyond corticosteroids: future prospects in the management of inflammation in COPD

    N. Roche

    2011-09-01

    Full Text Available Inflammation plays a central role in the pathophysiology of chronic obstructive pulmonary disease (COPD. Exposure to cigarette smoke induces the recruitment of inflammatory cells in the airways and stimulates innate and adaptive immune mechanisms. Airway inflammation is involved in increased bronchial wall thickness, increased bronchial smooth muscle tone, mucus hypersecretion and loss of parenchymal elastic structures. Oxidative stress impairs tissue integrity, accelerates lung ageing and reduces the efficacy of corticosteroids by decreasing levels of histone deacetylase-2. Protease–antiprotease imbalance impairs tissues and is involved in inflammatory processes. Inflammation is also present in the pulmonary artery wall and at the systemic level in COPD patients, and may be involved in COPD-associated comorbidities. Proximal airways inflammation contributes to symptoms of chronic bronchitis while distal and parenchymal inflammation relates to airflow obstruction, emphysema and hyperinflation. Basal levels of airways and systemic inflammation are increased in frequent exacerbators. Inhaled corticosteroids are much less effective in COPD than in asthma, which relates to the intrinsically poor reversibility of COPD-related airflow obstruction and to molecular mechanisms of resistance relating to oxidative stress. Ongoing research aims at developing new drugs targeting more intimately COPD-specific mechanisms of inflammation, hypersecretion and tissue destruction and repair. Among new anti-inflammatory agents, phosphodiesterase-4 inhibitors have been the first to emerge.

  14. Mecanismos adaptativos do sistema imunológico em resposta ao treinamento físico Adaptative mechanisms of the immune system in response to physical training

    Carol Góis Leandro

    2007-10-01

    Full Text Available O treinamento físico, de intensidade moderada, melhora os sistemas de defesa, enquanto que o treinamento intenso causa imunossupressão. Os mecanismos subjacentes estão associados à comunicação entre os sistemas nervoso, endócrino e imunológico, sugerindo vias autonômicas e modulação da resposta imune. Células do sistema imune, quando expostas a pequenas cargas de estresse, desenvolvem mecanismo de tolerância. Em muitos tecidos tem-se demonstrado que a resposta a situações agressivas parece ser atenuada pelo treinamento físico aplicado previamente, isto é, o treinamento induz tolerância para situações agressivas/estressantes. Nesta revisão são relatados estudos sugerindo os mecanismos adaptativos do sistema imunológico em resposta ao treinamento físico.Moderate physical training enhances the defense mechanisms, while intense physical training induces to immune suppression. The underlying mechanisms are associated with the link between nervous, endocrine, and immune systems. It suggests autonomic patterns and modulation of immune response. Immune cells, when exposed to regular bouts of stress, develop a mechanism of tolerance. In many tissues, it has been demonstrated that the response to aggressive conditions is attenuated by moderate physical training. Thus, training can induce tolerance to aggressive/stressful situations. In this review, studies suggesting the adaptation mechanisms of the immune system in response to physical training will be reported.

  15. Sublethal red tide toxin exposure in free-ranging manatees (Trichechus manatus) affects the immune system through reduced lymphocyte proliferation responses, inflammation, and oxidative stress.

    Walsh, Catherine J; Butawan, Matthew; Yordy, Jennifer; Ball, Ray; Flewelling, Leanne; de Wit, Martine; Bonde, Robert K

    2015-04-01

    The health of many Florida manatees (Trichechus manatus latirostris) is adversely affected by exposure to blooms of the toxic dinoflagellate, Karenia brevis. K. brevis blooms are common in manatee habitats of Florida's southwestern coast and produce a group of cyclic polyether toxins collectively referred to as red tide toxins, or brevetoxins. Although a large number of manatees exposed to significant levels of red tide toxins die, several manatees are rescued from sublethal exposure and are successfully treated and returned to the wild. Sublethal brevetoxin exposure may potentially impact the manatee immune system. Lymphocyte proliferative responses and a suite of immune function parameters in the plasma were used to evaluate effects of brevetoxin exposure on health of manatees rescued from natural exposure to red tide toxins in their habitat. Blood samples were collected from rescued manatees at Lowry Park Zoo in Tampa, FL and from healthy, unexposed manatees in Crystal River, FL. Peripheral blood leukocytes (PBL) isolated from whole blood were stimulated with T-cell mitogens, ConA and PHA. A suite of plasma parameters, including plasma protein electrophoresis profiles, lysozyme activity, superoxide dismutase (SOD) activity, and reactive oxygen/nitrogen (ROS/RNS) species, was also used to assess manatee health. Significant decreases (p<0.05) in lymphocyte proliferation were observed in ConA and PHA stimulated lymphocytes from rescued animals compared to non-exposed animals. Significant correlations were observed between oxidative stress markers (SOD, ROS/RNS) and plasma brevetoxin concentrations. Sublethal exposure to brevetoxins in the wild impacts some immune function components, and thus, overall health, in the Florida manatee. PMID:25678466

  16. Chronic Schistosome Infection Leads to Modulation of Granuloma Formation and Systemic Immune Suppression

    Steven K. Lundy

    2013-02-01

    Full Text Available Schistosome worms have been infecting humans for millennia, but it is only in the last half century that we have begun to understand the complexities of this inter-relationship. As our sophistication about the inner workings of every aspect of the immune system has increased, it has also become obvious that schistosome infections have broad ranging effects on nearly all of the innate and adaptive immune response mechanisms. Selective pressures on both the worms and their hosts, has no doubt led to co-evolution of protective mechanisms, particularly those that favor granuloma formation around schistosome eggs and immune suppression during chronic infection. The immune modulatory effects that chronic schistosome infection and egg deposition elicit have been intensely studied, not only because of their major implications to public health issues, but also due to the emerging evidence that schistosome infection may protect humans from severe allergies and autoimmunity. Mouse models of schistosome infection have been extremely valuable for studying immune modulation and regulation, and in the discovery of novel aspects of immunity. A progression of immune reactions occurs during granuloma formation ranging from innate inflammation, to activation of each branch of adaptive immune response, and culminating in systemic immune suppression and granuloma fibrosis. Although molecular factors from schistosome eggs have been identified as mediators of immune modulation and suppressive functions of T and B cells, much work is still needed to define the mechanisms of the immune alteration and determine whether therapies for asthma or autoimmunity could be developed from these pathways.

  17. Dual role of neutrophils in inflammation

    Pillay, J.

    2011-01-01

    Systemic inflammation is a hallmark of trauma, sepsis and various severe infectious diseases. Severe systemic inflammation can lead to inflammatory complications. The Acute Respiratory Distress Syndrome (ARDS) and Multiple Organ Dysfunction Syndrome (MODS) are seen after trauma and in sepsis and are accompanied by a high mortality and morbitidy. These complications are mediated by a hyperactive immune system. On the other hand, immune suppression is frequently seen following systemic inflamma...

  18. Lymphatic vessel contractile activity and intestinal inflammation

    Theresa F Wu; Wallace K MacNaughton; Pierre-Yves von der Weid

    2005-01-01

    Edema is a consistent observation in inflamatory bowel disease (IBD), and immune responses are inevitable in inflammation. Because the lymphatic system is an integral part of both tissue fluid homeostasis and immune reactions, it is likely that lymphatics play a role in the complex etiology of IBD. Despite the consistent findings that the lymphatic system is altered during gastrointestinal inflammation, the majority of studies conducted on the disease only mention the lymphatic system in pass...

  19. The Adaptor CARD9 Is Required for Adaptive but Not Innate Immunity to Oral Mucosal Candida albicans Infections

    Bishu, Shrinivas; Hernández-Santos, Nydiaris; Simpson-Abelson, Michelle R.; Huppler, Anna R; Conti, Heather R.; Ghilardi, Nico; Mamo, Anna J.; Sarah L Gaffen

    2014-01-01

    Oropharyngeal candidiasis (OPC [thrush]) is an opportunistic infection caused by the commensal fungus Candida albicans. OPC is common in individuals with HIV/AIDS, infants, patients on chemotherapy, and individuals with congenital immune defects. Immunity to OPC is strongly dependent on the interleukin-23 (IL-23)/IL-17R axis, as mice and humans with defects in IL-17R signaling (IL17F, ACT1, IL-17RA) or in genes that direct Th17 differentiation (STAT3, STAT1, CARD9) are prone to mucocutaneous ...

  20. Gut Microbiota and Inflammation

    Goran Molin

    2011-06-01

    Full Text Available Systemic and local inflammation in relation to the resident microbiota of the human gastro-intestinal (GI tract and administration of probiotics are the main themes of the present review. The dominating taxa of the human GI tract and their potential for aggravating or suppressing inflammation are described. The review focuses on human trials with probiotics and does not include in vitro studies and animal experimental models. The applications of probiotics considered are systemic immune-modulation, the metabolic syndrome, liver injury, inflammatory bowel disease, colorectal cancer and radiation-induced enteritis. When the major genomic differences between different types of probiotics are taken into account, it is to be expected that the human body can respond differently to the different species and strains of probiotics. This fact is often neglected in discussions of the outcome of clinical trials with probiotics.

  1. Does Hsp60 Provide a Link between Mitochondrial Stress and Inflammation in Diabetes Mellitus?

    2016-01-01

    The focus of this review is to summarise the known relationships between the expression of heat shock protein 60 (Hsp60) and its association with the pathogenesis of Type 1 and Type 2 diabetes mellitus. Hsp60 is a mitochondrial stress protein that is induced by mitochondrial impairment. It is known to be secreted from a number of cell types and circulating levels have been documented in both Types 1 and 2 diabetes mellitus patients. The biological significance of extracellular Hsp60, however, remains to be established. We will examine the links between Hsp60 and cellular anti- and proinflammatory processes and specifically address how Hsp60 appears to affect immune inflammation by at least two different mechanisms: as a ligand for innate immune receptors and as an antigen recognised by adaptive immune receptors. We will also look at the role of Hsp60 during immune cell activation in atherosclerosis, a significant risk factor during the pathogenesis of diabetes mellitus. PMID:27478851

  2. Type 2 Innate Lymphoid Cells: Friends or Foes—Role in Airway Allergic Inflammation and Asthma

    Abbas Pishdadian

    2012-01-01

    Full Text Available Innate-like lymphocytes (ILLs and innate lymphoid cells (ILCs are two newly characterized families of lymphocytes with limited and no rearranged antigen receptors, respectively. These soldiers provide a first line of defense against foreign insults by triggering a prompt innate immune response and bridging the gap of innate and adaptive immunity. Type 2 innate lymphoid cells (ILCs2 are newly identified members of the ILC family that play a key role in type 2 immune responses by prompt production of type 2 cytokines (especially IL-5 and IL-13 in response to antigen-induced IL-25/33 and by recruiting type 2 “immune franchise.” Regarding the two different roles of type 2 cytokines, helminth expulsion and type 2-related diseases, here we review the latest advances in ILC2 biology and examine the pivotal role of resident ILCs2 in allergen-specific airway inflammation and asthma.

  3. Immune tolerance to an intestine-adapted bacteria, Chryseobacterium sp., injected into the hemocoel of Protaetia brevitarsis seulensis

    Lee, Jiae; Hwang, Sejung; Cho, Saeyoull

    2016-01-01

    To explore the interaction of gut microbes and the host immune system, bacteria were isolated from the gut of Protaetia brevitarsis seulensis larvae. Chryseobacterium sp., Bacillus subtilis, Arthrobacter arilaitensis, Bacillus amyloliquefaciens, Bacillus megaterium, and Lysinibacillus xylanilyticus were cultured in vitro, identified, and injected in the hemocoel of P. brevitarsis seulensis larvae, respectively. There were no significant changes in phagocytosis-associated lysosomal formation or pathogen-related autophagosome in immune cells (granulocytes) from Chryseobacterium sp.-challenged larvae. Next, we examined changes in the transcription of innate immune genes such as peptidoglycan recognition proteins and antimicrobial peptides following infection with Chryseobacterium sp. PGRP-1 and -2 transcripts, which may be associated with melanization generated by prophenoloxidase (PPO), were either highly or moderately expressed at 24 h post-infection with Chryseobacterium sp. However, PGRP-SC2 transcripts, which code for bactericidal amidases, were expressed at low levels. With respect to antimicrobial peptides, only coleoptericin was moderately expressed in Chryseobacterium sp.-challenged larvae, suggesting maintenance of an optimum number of Chryseobacterium sp. All examined genes were expressed at significantly higher levels in larvae challenged with a pathogenic bacterium. Our data demonstrated that gut-inhabiting bacteria, the Chryseobacterium sp., induced a weaker immune response than other pathogenic bacteria, E. coli K12. PMID:27530146

  4. TLR adaptor MyD88 is essential for pathogen control during oral toxoplasma gondii infection but not adaptive immunity induced by a vaccine strain of the parasite.

    Sukhumavasi, Woraporn; Egan, Charlotte E; Warren, Amy L; Taylor, Gregory A; Fox, Barbara A; Bzik, David J; Denkers, Eric Y

    2008-09-01

    TLR adaptor MyD88 activation is important in host resistance to Toxoplasma gondii during i.p. infection, but the function of this signaling pathway during oral infection, in which mucosal immunity assumes a predominant role, has not been examined. In this study, we show that MyD88(-/-) mice fail to control the parasite and succumb within 2 wk of oral infection. Early during infection, T cell IFN-gamma production, recruitment of neutrophils and induction of p47 GTPase IGTP (Irgm3) in the intestinal mucosa were dependent upon functional MyD88. Unexpectedly, these responses were MyD88-independent later during acute infection. In particular, CD4(+) T cell IFN-gamma reached normal levels independently of MyD88, despite continued absence of IL-12 in these animals. The i.p. vaccination of MyD88(-/-) mice with an avirulent T. gondii uracil auxotroph elicited robust IFN-gamma responses and protective immunity to challenge with a high virulence T. gondii strain. Our results demonstrate that MyD88 is required to control Toxoplasma infection, but that the parasite can trigger adaptive immunity without the need for this TLR adaptor molecule. PMID:18714019

  5. Tissue-Expressed B7-H1 Critically Controls Intestinal Inflammation

    Lisa Scandiuzzi

    2014-02-01

    Full Text Available B7-H1 (PD-L1 on immune cells plays an important role in T cell coinhibition by binding its receptor PD-1. Here, we show that both human and mouse intestinal epithelium express B7-H1 and that B7-H1-deficient mice are highly susceptible to dextran sodium sulfate (DSS- or trinitrobenzenesulfonic acid (TNBS-induced gut injury. B7-H1 deficiency during intestinal inflammation leads to high mortality and morbidity, which are associated with severe pathological manifestations in the colon, including loss of epithelial integrity and overgrowth of commensal bacteria. Results from bone marrow chimeric and knockout mice show that B7-H1 expressed on intestinal parenchyma, but not on hematopoietic cells, controls intestinal inflammation in an adaptive immunity-independent fashion. Finally, we demonstrate that B7-H1 dampened intestinal inflammation by inhibiting tumor necrosis factor α (TNF-α production and by stimulating interleukin 22 secretion from CD11c+CD11b+ lamina propria cells. Thus, our data uncover a mechanism through which intestinal tissue-expressed B7-H1 functions as an essential ligand for innate immune cells to prevent gut inflammation.

  6. Antibacterial immune competence of honey bees (Apis mellifera is adapted to different life stages and environmental risks.

    Heike Gätschenberger

    Full Text Available The development of all honey bee castes proceeds through three different life stages all of which encounter microbial infections to a various extent. We have examined the immune strength of honey bees across all developmental stages with emphasis on the temporal expression of cellular and humoral immune responses upon artificial challenge with viable Escherichia coli bacteria. We employed a broad array of methods to investigate defence strategies of infected individuals: (a fate of bacteria in the haemocoel; (b nodule formation and (c induction of antimicrobial peptides (AMPs. Newly emerged adult worker bees and drones were able to activate efficiently all examined immune reactions. The number of viable bacteria circulating in the haemocoel of infected bees declined rapidly by more than two orders of magnitude within the first 4-6 h post-injection (p.i., coinciding with the occurrence of melanised nodules. Antimicrobial activity, on the other hand, became detectable only after the initial bacterial clearance. These two temporal patterns of defence reactions very likely represent the constitutive cellular and the induced humoral immune response. A unique feature of honey bees is that a fraction of worker bees survives the winter season in a cluster mostly engaged in thermoregulation. We show here that the overall immune strength of winter bees matches that of young summer bees although nodulation reactions are not initiated at all. As expected, high doses of injected viable E.coli bacteria caused no mortality in larvae or adults of each age. However, drone and worker pupae succumbed to challenge with E.coli even at low doses, accompanied by a premature darkening of the pupal body. In contrast to larvae and adults, we observed no fast clearance of viable bacteria and no induction of AMPs but a rapid proliferation of E.coli bacteria in the haemocoel of bee pupae ultimately leading to their death.

  7. An imbalance between innate and adaptive immune cells at the maternal-fetal interface occurs prior to endotoxin-induced preterm birth.

    Arenas-Hernandez, Marcia; Romero, Roberto; St Louis, Derek; Hassan, Sonia S; Kaye, Emily B; Gomez-Lopez, Nardhy

    2016-07-01

    Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. A transition from an anti-inflammatory state to a pro-inflammatory state in the mother and at the maternal-fetal interface has been implicated in the pathophysiology of microbial-induced preterm labor. However, it is unclear which immune cells mediate this transition. We hypothesized that an imbalance between innate and adaptive immune cells at the maternal-fetal interface will occur prior to microbial-induced preterm labor. Using an established murine model of endotoxin-induced PTB, our results demonstrate that prior to delivery there is a reduction of CD4+ regulatory T cells (Tregs) in the uterine tissues. This reduction is neither linked to a diminished number of Tregs in the spleen, nor to an impaired production of IL10, CCL17, or CCL22 by the uterine tissues. Endotoxin administration to pregnant mice does not alter effector CD4+ T cells at the maternal-fetal interface. However, it causes an imbalance between Tregs (CD4+ and CD8+), effector CD8+ T cells, and Th17 cells in the spleen. In addition, endotoxin administration to pregnant mice leads to an excessive production of CCL2, CCL3, CCL17, and CCL22 by the uterine tissues as well as abundant neutrophils. This imbalance in the uterine microenvironment is accompanied by scarce APC-like cells such as macrophages and MHC II+ neutrophils. Collectively, these results demonstrate that endotoxin administration to pregnant mice causes an imbalance between innate and adaptive immune cells at the maternal-fetal interface. PMID:25849119

  8. LC-MS/MS analysis of visceral and subcutaneous adipose tissue proteomes in young goats with focus on innate immunity and inflammation related proteins

    Restelli, Laura; Codrea, Marius Cosmin; Savoini, Giovanni;

    2014-01-01

    protein and gene expression patterns. In ruminants, fat tissues play important biological roles not only for animal health, but also for quality and gain in meat and milk production. Yet very few studies have explored the ruminant adipose tissue proteomes. The aim of our study was to compare subcutaneous...... and visceral adipose tissues of goat, focusing on proteins involved in immune and inflammatory response. A 2-D LC-MS/MS approach followed by cluster analysis shows a clear distinction between subcutaneous and visceral fat tissue proteomes, and qualitative RT-PCR based analysis of 30 potential...... adipokines further confirmed the individual expression patterns of 26 of these, including 7 whose mRNA expression was observed for the first time in adipose tissues. This study provides a first description of adipose tissue proteomes in goat, and presents observations on novel proteins related to metabolic...

  9. Innate immune responses and rapid control of inflammation in African green monkeys treated or not with interferon-alpha during primary SIVagm infection.

    Béatrice Jacquelin

    2014-07-01

    Full Text Available Chronic immune activation (IA is considered as the driving force of CD4(+ T cell depletion and AIDS. Fundamental clues in the mechanisms that regulate IA could lie in natural hosts of SIV, such as African green monkeys (AGMs. Here we investigated the role of innate immune cells and IFN-α in the control of IA in AGMs. AGMs displayed significant NK cell activation upon SIVagm infection, which was correlated with the levels of IFN-α. Moreover, we detected cytotoxic NK cells in lymph nodes during the early acute phase of SIVagm infection. Both plasmacytoid and myeloid dendritic cell (pDC and mDC homing receptors were increased, but the maturation of mDCs, in particular of CD16+ mDCs, was more important than that of pDCs. Monitoring of 15 cytokines showed that those, which are known to be increased early in HIV-1/SIVmac pathogenic infections, such as IL-15, IFN-α, MCP-1 and CXCL10/IP-10, were significantly increased in AGMs as well. In contrast, cytokines generally induced in the later stage of acute pathogenic infection, such as IL-6, IL-18 and TNF-α, were less or not increased, suggesting an early control of IA. We then treated AGMs daily with high doses of IFN-α from day 9 to 24 post-infection. No impact was observed on the activation or maturation profiles of mDCs, pDCs and NK cells. There was also no major difference in T cell activation or interferon-stimulated gene (ISG expression profiles and no sign of disease progression. Thus, even after administration of high levels of IFN-α during acute infection, AGMs were still able to control IA, showing that IA control is independent of IFN-α levels. This suggests that the sustained ISG expression and IA in HIV/SIVmac infections involves non-IFN-α products.

  10. A co culture approach show that polyamine turnover is affected during inflammation in Atlantic salmon immune and liver cells and that arginine and LPS exerts opposite effects on p38MAPK signaling.

    Holen, Elisabeth; Espe, Marit; Andersen, Synne M; Taylor, Richard; Aksnes, Anders; Mengesha, Zebasil; Araujo, Pedro

    2014-04-01

    This study assess which pathways and molecular processes are affected by exposing salmon head kidney cells or liver cells to arginine supplementation above the established requirements for growth support. In addition to the conventional mono cultures of liver and head kidney cells, co cultures of the two cell types were included in the experimental set up. Responses due to elevated levels of arginine were measured during inflammatory (lipopolysaccharide/LPS) and non -inflammatory conditions. LPS up regulated the genes involved in polyamine turnover; ODC (ornithine decarboxylase), SSAT (spermidine/spermine-N1-acetyltransferase) and SAMdc (S-adenosyl methionine decarboxylase) in head kidney cells when co cultured with liver cells. Regardless of treatment, liver cells in co culture up regulated ODC and down regulated SSAT when compared to liver mono cultures. This suggests that polyamines have anti-inflammatory properties and that both salmon liver cells and immune cells seem to be involved in this process. The transcription of C/EBP β/CCAAT, increased during inflammation in all cultures except for liver mono cultures. The observed up regulation of this gene may be linked to glucose transport due to the highly variable glucose concentrations found in the cell media. PPARα transcription was also increased in liver cells when receiving signals from head kidney cells. Gene transcription of Interleukin 1β (IL-1β), Interleukin-8 (IL-8), cyclooxygenase 2 (COX2) and CD83 were elevated during LPS treatment in all the head kidney cell cultures while arginine supplementation reduced IL-1β and IL-8 transcription in liver cells co cultured with head kidney cells. This is probably connected to p38MAPK signaling as arginine seem to affect p38MAPK signaling contrary to the LPS induced p38MAPK signaling, suggesting anti-inflammatory effects of arginine/arginine metabolites. This paper shows that co culturing these two cell types reveals the connection between metabolism and

  11. Basophils in inflammation.

    Schwartz, Christian; Eberle, Joerg U; Voehringer, David

    2016-05-01

    Basophils are functionally closely related to mast cells. Both cell types express the high-affinity IgE receptor (FcεRI) and rapidly release preformed mediator from intracellular stores upon IgE-mediated activation. However, in contrast to mast cells basophils finish their maturation in the bone marrow and have a lifespan of only 2-3 days. Basophil numbers increase in response to IL-3 or TSLP and migrate into tissues to promote type 2 immune responses. Here we review recent advances regarding the pro- and anti-inflammatory functions of basophils in murine models and human allergic inflammation of the skin, lung and intestine. PMID:25959388

  12. Role of platelets in inflammation

    Kadir Serkan Yalçın

    2012-09-01

    Full Text Available Inflammation, which is extremely useful process for humanbody is the response of living vascular tissues topathological phenomena that removes the pathogens andinitiates the healing procedure. Microorganisms, physicaltrauma, chemical, mechanical, irradiation, or thermal injury,ischemia and immune reactions are most commoncauses of this exceptionally important event for humanbody. Platelets are non-nucleated cells in blood that producedin bone marrow as derived from megakaryocytes.Apart from stop bleeding and achieving hemostasis thereare incredibly important roles of platelets in inflammation.Platelets contain important mediators for inflammationlike neutrophils or macrophages and can alter the courseof mechanism. In this article changing platelet function ininflammation and the effect of these functions to the processof inflammation will be discussed.Key words: Platelet, inflammation, cytokines

  13. Innate immune reconstitution with suppression of HIV-1

    Scully, Eileen P.; Lockhart, Ainsley; Garcia-Beltran, Wilfredo; Palmer, Christine D.; Musante, Chelsey; Rosenberg, Eric; Allen, Todd M.; Chang, J. Judy; Bosch, Ronald J.; Altfeld, Marcus

    2016-01-01

    Progressive HIV-1 infection leads to both profound immune suppression and pathologic inflammation in the majority of infected individuals. While adaptive immune dysfunction, as evidenced by CD4+ T cell depletion and exhaustion, has been extensively studied, less is known about the functional capacity of innate immune cell populations in the context of HIV-1 infection. Given the broad susceptibility to opportunistic infections and the dysregulated inflammation observed in progressive disease, we hypothesized that there would be significant changes in the innate cellular responses. Using a cohort of patients with multiple samplings before and after antiretroviral therapy (ART) initiation, we demonstrated increased responses to innate immune stimuli following viral suppression, as measured by the production of inflammatory cytokines. Plasma viral load itself had the strongest association with this change in innate functional capacity. We further identified epigenetic modifications in the TNFA promoter locus in monocytes that are associated with viremia, suggesting a molecular mechanism for the observed changes in innate immune function following initiation of ART. These data indicate that suppression of HIV-1 viremia is associated with changes in innate cellular function that may in part determine the restoration of protective immune responses. PMID:27158667

  14. Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma

    He, GaiXia; Zhang, Henghui; Zhou, JinXue; Wang, Beibei; Chen, Yanhui; Kong, Yaxian; Xie, Xingwang; Wang, Xueyan; Fei, Ran; Wei, Lai; Chen, Hongsong; ZENG, HUI

    2015-01-01

    Background PD-L1 expression on neutrophils contributes to the impaired immune response in infectious disease, but the detailed role of PD-L1 expression on neutrophils in HCC remains unclear. Methods We investigated the phenotype and morphology of neutrophils infiltrated in tumour tissues from both patients with HCC and hepatoma-bearing mice. Results We found that neutrophils dominantly infiltrated in the peritumoural region. The neutrophil-to-T cell ratio (NLR) was higher in peritumoural tiss...

  15. Role of the effector and regulatory arms of the adaptative immune response in the pathophysiology of experimental asthma

    Amor Carro, Óscar

    2014-01-01

    Classic murine models of experimental asthma based on intraperitoneal sensitization followed by airway challenge do not reflect the way in which humans acquire allergic disease to airborne allergens. The interaction of the airway mucosa with the allergens may be essential for the triggering of the subsequent immune response. In the present work, we developed a murine model of allergic disease based on primary airway exposure to antigen followed by continuous airway challenge. Foll...

  16. Systemic Transcriptional Alterations of Innate and Adaptive Immune Signaling Pathways in Atherosclerosis, Ischemia Stroke, and Myocardial Infarction

    Barr, Taura L.; VanGilder, Reynal L.; Seiberg, Ryan; Petrone, Ashely; Chantler, Paul D.; Huang, Chiang-Ching

    2015-01-01

    Background Transcriptional profiles are available for a variety of cardiovascular-related diseases. The goal of this study was to compare blood transcriptional profiles of the Toll-like receptor (TLR), T-cell receptor (TCR), and B-cell receptor (BCR) signaling pathways in asymptomatic atherosclerosis, acute ischemic stroke, and myocardial infarction patients to identify common mechanisms of immune regulation and their association with epigenetic regulation. Methods and results Peripheral bloo...

  17. From Innate to Adaptive Immune Response in Muscular Dystrophies and Skeletal Muscle Regeneration: The Role of Lymphocytes

    Luca Madaro

    2014-01-01

    Full Text Available Skeletal muscle is able to restore contractile functionality after injury thanks to its ability to regenerate. Following muscle necrosis, debris is removed by macrophages, and muscle satellite cells (MuSCs, the muscle stem cells, are activated and subsequently proliferate, migrate, and form muscle fibers restoring muscle functionality. In most muscle dystrophies (MDs, MuSCs fail to properly proliferate, differentiate, or replenish the stem cell compartment, leading to fibrotic deposition. However, besides MuSCs, interstitial nonmyogenic cells and inflammatory cells also play a key role in orchestrating muscle repair. A complete understanding of the complexity of these mechanisms should allow the design of interventions to attenuate MDs pathology without disrupting regenerative processes. In this review we will focus on the contribution of immune cells in the onset and progression of MDs, with particular emphasis on Duchenne muscular dystrophy (DMD. We will briefly summarize the current knowledge and recent advances made in our understanding of the involvement of different innate immune cells in MDs and will move on to critically evaluate the possible role of cell populations within the acquired immune response. Revisiting previous observations in the light of recent evidence will likely change our current view of the onset and progression of the disease.

  18. From Innate to Adaptive Immune Response in Muscular Dystrophies and Skeletal Muscle Regeneration: The Role of Lymphocytes

    Madaro, Luca; Bouché, Marina

    2014-01-01

    Skeletal muscle is able to restore contractile functionality after injury thanks to its ability to regenerate. Following muscle necrosis, debris is removed by macrophages, and muscle satellite cells (MuSCs), the muscle stem cells, are activated and subsequently proliferate, migrate, and form muscle fibers restoring muscle functionality. In most muscle dystrophies (MDs), MuSCs fail to properly proliferate, differentiate, or replenish the stem cell compartment, leading to fibrotic deposition. However, besides MuSCs, interstitial nonmyogenic cells and inflammatory cells also play a key role in orchestrating muscle repair. A complete understanding of the complexity of these mechanisms should allow the design of interventions to attenuate MDs pathology without disrupting regenerative processes. In this review we will focus on the contribution of immune cells in the onset and progression of MDs, with particular emphasis on Duchenne muscular dystrophy (DMD). We will briefly summarize the current knowledge and recent advances made in our understanding of the involvement of different innate immune cells in MDs and will move on to critically evaluate the possible role of cell populations within the acquired immune response. Revisiting previous observations in the light of recent evidence will likely change our current view of the onset and progression of the disease. PMID:25028653

  19. WAP domain proteins as modulators of mucosal immunity.

    Wilkinson, Thomas S; Roghanian, Ali; Simpson, Alexander John; Sallenave, Jean-Michel

    2011-10-01

    WAP (whey acidic protein) is an important whey protein present in milk of mammals. This protein has characteristic domains, rich in cysteine residues, called 4-DSC (four-disulfide core domain). Other proteins, mainly present at mucosal surfaces, have been shown to also possess these characteristic WAP-4-DSC domains. The present review will focus on two WAP-4-DSC containing proteins, namely SLPI (secretory leucocyte protease inhibitor) and trappin-2/elafin. Although first described as antiproteases able to inhibit in particular host neutrophil proteases [NE (neutrophil elastase), cathepsin-G and proteinase-3] and as such, able to limit maladaptive tissue damage during inflammation, it has become apparent that these molecules have a variety of other functions (direct antimicrobial activity, bacterial opsonization, induction of adaptive immune responses, promotion of tissue repair, etc.). After providing information about the 'classical' antiproteasic role of these molecules, we will discuss the evidence pertaining to their pleiotropic functions in inflammation and immunity. PMID:21936824

  20. Immune System and Its Link to Rheumatic Diseases

    ... Disease The Immune System & Its Link to Rheumatic Disease The Immune System and Its Link to Rheumatic Disease Fast ... cells. This leads to illnesses called autoimmune (self-immune) diseases such as rheumatoid arthritis (inflammation of the joints), ...

  1. Innate and Adaptive Immune Response to Pneumonia Virus of Mice in a Resistant and a Susceptible Mouse Strain

    Ellen R. T. Watkiss

    2013-01-01

    Full Text Available Respiratory syncytial virus (RSV is the leading cause of infant bronchiolitis. The closely related pneumonia virus of mice (PVM causes a similar immune-mediated disease in mice, which allows an analysis of host factors that lead to severe illness. This project was designed to compare the immune responses to lethal and sublethal doses of PVM strain 15 in Balb/c and C57Bl/6 mice. Balb/c mice responded to PVM infection with an earlier and stronger innate response that failed to control viral replication. Production of inflammatory cyto- and chemokines, as well as infiltration of neutrophils and IFN-γ secreting natural killer cells into the lungs, was more predominant in Balb/c mice. In contrast, C57Bl/6 mice were capable of suppressing both viral replication and innate inflammatory responses. After a sublethal infection, PVM-induced IFN-γ production by splenocytes was stronger early during infection and weaker at late time points in C57Bl/6 mice when compared to Balb/c mice. Furthermore, although the IgG levels were similar and the mucosal IgA titres lower, the virus neutralizing antibody titres were higher in C57Bl/6 mice than in Balb/c mice. Overall, the difference in susceptibility of these two strains appeared to be related not to an inherent T helper bias, but to the capacity of the C57Bl/6 mice to control both viral replication and the immune response elicited by PVM.

  2. Rabies Virus Expressing Dendritic Cell-Activating Molecules Enhances the Innate and Adaptive Immune Response to Vaccination ▿

    Wen, Yongjun; Wang, Hualei; Wu, Hua; Yang, Fuhe; Tripp, Ralph A.; Hogan, Robert J.; Fu, Zhen F.

    2010-01-01

    Our previous studies indicated that recruitment and/or activation of dendritic cells (DCs) is important in enhancing the protective immune responses against rabies virus (RABV) (L. Zhao, H. Toriumi, H. Wang, Y. Kuang, X. Guo, K. Morimoto, and Z. F. Fu, J. Virol. 84:9642-9648). To address the importance of DC activation for RABV vaccine efficacy, the genes for several DC recruitment and/or activation molecules, e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage-derived...

  3. Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration.

    Sankowski, Roman; Mader, Simone; Valdés-Ferrer, Sergio Iván

    2015-01-01

    The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system (CNS) coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The CNS feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. Cytokines, chemokines, and damage-associated soluble mediators of systemic inflammation can also gain access to the CNS via blood flow. In response to systemic inflammation, those soluble mediators can access directly through the circumventricular organs, as well as open the blood-brain barrier. The resulting translocation of inflammatory mediators can interfere with neuronal and glial well-being, leading to a break of balance in brain homeostasis. This in turn results in cognitive and behavioral manifestations commonly present during acute infections - including anorexia, malaise, depression, and decreased physical activity - collectively known as the sickness behavior (SB). While SB manifestations are transient and self-limited, under states of persistent systemic inflammatory response the cognitive and behavioral changes can become permanent. For example, cognitive decline is almost universal in sepsis survivors, and a common finding in patients with systemic lupus erythematosus. Here, we review recent genetic evidence suggesting an association between neurodegenerative disorders and persistent immune activation; clinical and experimental evidence indicating previously unidentified immune-mediated pathways of neurodegeneration; and novel immunomodulatory targets and their potential relevance for neurodegenerative disorders. PMID:25698933

  4. Systemic Inflammation and the Brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration.

    Roman Sankowski

    2015-02-01

    Full Text Available The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The central nervous system (CNS feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. Cytokines, chemokines, damage-associated soluble mediators of systemic inflammation can also gain access to the CNS via blood flow. In response to systemic inflammation, those soluble mediators can access directly through the circumventricular organs, as well as open the blood-brain barrier (BBB. The resulting translocation of inflammatory mediators can interfere with neuronal and glial well-being, leading to a break of balance in brain homeostasis. This in turn results in cognitive and behavioral manifestations commonly present during acute infections -including anorexia, malaise, depression, and decreased physical activity- collectively known as the sickness behavior (SB. While SB manifestations are transient and self-limited, under states of persistent systemic inflammatory response the cognitive and behavioral changes can become permanent. For example, cognitive decline is almost universal in sepsis survivors, and a common finding in patients with systemic lupus erythematosus (SLE. Here, we review recent genetic evidence suggesting an association between neurodegenerative disorders and persistent immune activation; clinical and experimental evidence indicating previously unidentified immune-mediated pathways of neurodegeneration; and novel immunomodulatory targets and their potential relevance for neurodegenerative disorders.

  5. Endoplasmic reticulum aminopeptidase 1 function and its pathogenic role in regulating innate and adaptive immunity in cancer and major histocompatibility complex class I-associated autoimmune diseases.

    Fruci, D; Romania, P; D'Alicandro, V; Locatelli, F

    2014-08-01

    Major histocompatibility complex (MHC) class I molecules present antigenic peptides on the cell surface to alert natural killer (NK) cells and CD8(+) T cells for the presence of abnormal intracellular events, such as virus infection or malignant transformation. The generation of antigenic peptides is a multistep process that ends with the trimming of N-terminal extensions in the endoplasmic reticulum (ER) by aminopeptidases ERAP1 and ERAP2. Recent studies have highlighted the potential role of ERAP1 in reprogramming the immunogenicity of tumor cells in order to elicit innate and adaptive antitumor immune responses, and in conferring susceptibility to autoimmune diseases in predisposed individuals. In this review, we will provide an overview of the current knowledge about the role of ERAP1 in MHC class I antigen processing and how its manipulation may constitute a promising tool for cancer immunotherapy and treatment of MHC class I-associated autoimmune diseases. PMID:25066018

  6. Adaptive Immune Responses in a Multiple Sclerosis Patient with Acute Varicella-Zoster Virus Reactivation during Treatment with Fingolimod

    Andrea Harrer

    2015-09-01

    Full Text Available Fingolimod, an oral sphingosine 1-phosphate (S1P receptor modulator, is approved for the treatment of relapsing forms of multiple sclerosis (MS. The interference with S1P signaling leads to retention particularly of chemokine receptor-7 (CCR7 expressing T cells in lymph nodes. The immunological basis of varicella zoster virus (VZV infections during fingolimod treatment is unclear. Here, we studied the dynamics of systemic and intrathecal immune responses associated with symptomatic VZV reactivation including cessation of fingolimod and initiation of antiviral therapy. Key features in peripheral blood were an about two-fold increase of VZV-specific IgG at diagnosis of VZV reactivation as compared to the previous months, a relative enrichment of effector CD4+ T cells (36% versus mean 12% in controls, and an accelerated reconstitution of absolute lymphocytes counts including a normalized CD4+/CD8+ ratio and reappearance of CCR7+ T cells. In cerebrospinal fluid (CSF the lymphocytic pleocytosis and CD4+/CD8+ ratios at diagnosis of reactivation and after nine days of fingolimod discontinuation remained unchanged. During this time CCR7+ T cells were not observed in CSF. Further research into fingolimod-associated VZV reactivation and immune reconstitution is mandatory to prevent morbidity and mortality associated with this potentially life-threatening condition.

  7. HIV-1 Adaptation to Antigen Processing Results in Population-Level Immune Evasion and Affects Subtype Diversification

    Tenzer, Stefan; Crawford, Hayley; Pymm, Phillip;

    2014-01-01

    subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of......The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8(+) T cell responses to two HIV-Gag regions are uniquely associated with delayed disease progression only in patients expressing a few rare HLA class I variants when these...... regions encode epitopes presented by ~30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ~60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at...

  8. Comparison of vaccines for induction of heterosubtypic immunity to influenza A virus: cold-adapted vaccine versus DNA prime-adenovirus boost strategies.

    Lo, Chia-Yun; Wu, Zhengqi; Misplon, Julia A; Price, Graeme E; Pappas, Claudia; Kong, Wing-Pui; Tumpey, Terrence M; Epstein, Suzanne L

    2008-04-16

    Influenza epidemics or pandemics can arise for which strain- or subtype-matched vaccines are unavailable. Heterosubtypic immunity (Het-I) targeting conserved influenza A antigens could reduce morbidity and mortality during preparation of matched vaccines. Various vaccines inducing Het-I in animals have been studied separately using different viruses and conditions, but effectiveness for inducing Het-I has not been directly compared. The present studies compared immunization with cold-adapted (ca) viruses to DNA prime-recombinant adenovirus (rAd) boost vaccination to conserved antigens nucleoprotein (NP), matrix-2 (M2), or A/NP+M2. Both ca and DNA-rAd vaccinations induced antibody and T cell responses, and protected against lethal H1N1 challenge. Only A/NP+M2 DNA-rAd protected against challenge with highly pathogenic A/Vietnam/1203/2004 (H5N1); ca vaccine did not. Existing ca vaccines may provide some Het-I, but experimental vaccination focusing on conserved antigens was more effective in this model for protection against a divergent, highly pathogenic virus. PMID:18378366

  9. This paper is the winner of an SFB Award in the Hospital Intern, Residency category: Peptide biomaterials raising adaptive immune responses in wound healing contexts.

    Vigneswaran, Yalini; Han, Huifang; De Loera, Roberto; Wen, Yi; Zhang, Xing; Sun, Tao; Mora-Solano, Carolina; Collier, Joel H

    2016-08-01

    Biomaterials used in the context of tissue engineering or wound repair are commonly designed to be "nonimmunogenic." However, previously it has been observed that self-assembled peptide nanofiber materials are noninflammatory despite their immunogenicity, suggesting that they may be appropriate for use in wound-healing contexts. To test this hypothesis, mice were immunized with epitope-containing peptide self-assemblies until they maintained high antibody titers against the material, then gels of the same peptide assemblies were applied within full-thickness dermal wounds. In three different murine dermal-wounding models with different baseline healing rates, even significantly immunogenic peptide assemblies did not delay healing. Conversely, adjuvanted peptide assemblies, while raising similar antibody titers to unadjuvanted assemblies, did delay wound healing. Analysis of the healing wounds indicated that compared to adjuvanted peptide assemblies, the unadjuvanted assemblies exhibited a progression of the dominant T-cell subset from CD4(+) to CD8(+) cells in the wound, and CD4(+) cell populations displayed a more Th2-slanted response. These findings illustrate an example of a significant antibiomaterial adaptive immune response that does not adversely affect wound healing despite ongoing antibody production. This material would thus be considered "immunologically compatible" in this specific context rather than "nonimmunogenic," a designation that is expected to apply to a range of other protein- and peptide-based biomaterials in wound-healing and tissue-engineering applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1853-1862, 2016. PMID:27129604

  10. An adaptive immune response driven by mature, antigen-experienced T and B cells within the microenvironment of oral squamous cell carcinoma.

    Quan, Hongzhi; Fang, Liangjuan; Pan, Hao; Deng, Zhiyuan; Gao, Shan; Liu, Ousheng; Wang, Yuehong; Hu, Yanjia; Fang, Xiaodan; Yao, Zhigang; Guo, Feng; Lu, Ruohuang; Xia, Kun; Tang, Zhangui

    2016-06-15

    Lymphocyte infiltrates have been observed in the microenvironment of oral cancer; however, little is known about whether the immune response of the lymphocyte infiltrate affects tumor biology. For a deeper understanding of the role of the infiltrating-lymphocytes in oral squamous cell carcinoma (OSCC), we characterized the lymphocyte infiltrate repertoires and defined their features. Immunohistochemistry revealed considerable T and B cell infiltrates and lymphoid follicles with germinal center-like structures within the tumor microenvironment. Flow cytometry demonstrated that populations of antigen-experienced CD4+ and CD8+ cells were present, as well as an enrichment of regulatory T cells; and T cells expressing programmed death-1 (PD-1) and T cell Ig and mucin protein-3 (Tim-3), indicative of exhaustion, within the tumor microenvironment. Characterization of tumor-infiltrating B cells revealed clear evidence of antigen exposure, in that the cardinal features of an antigen-driven B cell response were present, including somatic mutation, clonal expansion, intraclonal variation and isotype switching. Collectively, our results point to an adaptive immune response occurring within the OSCC microenvironment, which may be sustained by the expression of specific antigens in the tumor. PMID:26815146

  11. Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies.

    Guillerey, Camille; Nakamura, Kyohei; Vuckovic, Slavica; Hill, Geoffrey R; Smyth, Mark J

    2016-04-01

    Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM. PMID:26801219

  12. Community Immunity (Herd Immunity)

    ... Read more information on enabling JavaScript. Skip Content Marketing Share this: Main Content Area ​Community Immunity ("Herd" ... population is immunized, protecting most community members. The principle of community immunity applies to control of a ...

  13. Yersinia enterocolitica targets cells of the innate and adaptive immune system by injection of Yops in a mouse infection model.

    Martin Köberle

    2009-08-01

    Full Text Available Yersinia enterocolitica (Ye evades the immune system of the host by injection of Yersinia outer proteins (Yops via a type three secretion system into host cells. In this study, a reporter system comprising a YopE-beta-lactamase hybrid protein and a fluorescent staining sensitive to beta-lactamase cleavage was used to track Yop injection in cell culture and in an experimental Ye mouse infection model. Experiments with GD25, GD25-beta1A, and HeLa cells demonstrated that beta1-integrins and RhoGTPases play a role for Yop injection. As demonstrated by infection of splenocyte suspensions in vitro, injection of Yops appears to occur randomly into all types of leukocytes. In contrast, upon infection of mice, Yop injection was detected in 13% of F4/80(+, 11% of CD11c(+, 7% of CD49b(+, 5% of Gr1(+ cells, 2.3% of CD19(+, and 2.6% of CD3(+ cells. Taking the different abundance of these cell types in the spleen into account, the highest total number of Yop-injected cells represents B cells, particularly CD19(+CD21(+CD23(+ follicular B cells, followed by neutrophils, dendritic cells, and macrophages, suggesting a distinct cellular tropism of Ye. Yop-injected B cells displayed a significantly increased expression of CD69 compared to non-Yop-injected B cells, indicating activation of these cells by Ye. Infection of IFN-gammaR (receptor- and TNFRp55-deficient mice resulted in increased numbers of Yop-injected spleen cells for yet unknown reasons. The YopE-beta-lactamase hybrid protein reporter system provides new insights into the modulation of host cell and immune responses by Ye Yops.

  14. A pox on thee! Manipulation of the host immune system by myxoma virus and implications for viral-host co-adaptation.

    Zúñiga, Martha C

    2002-09-01

    The poxviruses have evolved a diverse array of proteins which serve to subvert innate and adaptive host responses that abort or at least limit viral infections. Myxoma virus and its rabbit host are considered to represent an ideal poxvirus-host system in which to study the effects of these immunomodulatory proteins. Studies of laboratory rabbits (Oryctolagus cuniculus) infected with gene knockout variants of myxoma virus have provided compelling evidence that several myxoma virus gene products contribute to the pathogenic condition known as myxomatosis. However, myxomatosis, which is characterized by skin lesions, systemic immunosuppression, and a high mortality rate, does not occur in the virus' natural South American host, Sylvilogus brasiliensis. Moreover, in Australia where myxoma virus was willfully introduced to control populations of O. cuniculus, myxomatosis-resistant rabbits emerged within a year of myxoma virus introduction into the field. In this review I discuss the characterized immunomodulatory proteins of myxoma virus, their biochemical properties, their pathogenic effects in laboratory rabbits, the role of the host immune system in the susceptibility or resistance to myxomatosis, and the evidence that immunomodulatory genes may have been attenuated during the co-adaptation of myxoma virus and O. cuniculus in Australia. PMID:12297325

  15. The influence of dietary β-glucans on the adaptive and innate immune responses of European sea bass (Dicentrarchus labrax vaccinated against vibriosis

    Pier Paolo Gatta

    2010-01-01

    Full Text Available The effects of feeding 1,3/1,6 β-glucans on the innate and the adaptive immune responses of European sea bass (Dicentrarchus labrax was investigated. Two experiments were carried out during the study. In the first, a number of non-specific immune parameters were examined at 4, 7, 10, 14, 21 and 25 days of feeding fish with a semipurified diet containing Macrogard ©, a commercially available form of 1,3/1,6 β-glucans. The respiratory burst activity of head kidney macrophages isolated from the different groups of fish fed the immunostimulant peaked and subsequently decreased at different times during the experiment. Head kidney macrophages from fish fed 250 ppm β-glucans had a statistically higher level of respiratory burst activity at Day 21 of feeding compared with fish fed no immunostimulant. No statistical differences were observed in lyzozyme activity during this trial. In the second experiment, the effect of feeding 1,3/1,6 β-glucans on the immune response of fish to an alginate-encapsulated Vibrio vaccine administered orally was examined. Respiratory burst of head kidney macrophages and serum lysozyme activity decreased in all fish over the course of the trial, while serum lysozyme activity was considerably lower than values obtained in the first experiment. Fish vaccinated orally had significant increases in antibody response by Week 2 post-vaccination, but β-glucans did not appear to affect these levels. Vaccination may have resulted in activating the immune system as a whole, thus masking any difference in immunostimulation by the β-glucans. It may be that the optimal doses and timing of β-glucans administration is different when the immunostimulant is administered alone or in combination with the vaccine. In conclusion, European sea bass can be immunomodulated with oral administration of β-glucan. Optimal doses and administration times have been established when β-glucans are fed alone, although further studies are needed to

  16. Size effects of latex nanomaterials on lung inflammation in mice

    Effects of nano-sized materials (nanomaterials) on sensitive population have not been well elucidated. This study examined the effects of pulmonary exposure to (latex) nanomaterials on lung inflammation related to lipopolysaccharide (LPS) or allergen in mice, especially in terms of their size-dependency. In protocol 1, ICR male mice were divided into 8 experimental groups that intratracheally received a single exposure to vehicle, latex nanomaterials (250 μg/animal) with three sizes (25, 50, and 100 nm), LPS (75 μg/animal), or LPS plus latex nanomaterials. In protocol 2, ICR male mice were divided into 8 experimental groups that intratracheally received repeated exposure to vehicle, latex nanomaterials (100 μg/animal), allergen (ovalbumin: OVA; 1 μg/animal), or allergen plus latex nanomaterials. In protocol 1, latex nanomaterials with all sizes exacerbated lung inflammation elicited by LPS, showing an overall trend of amplified lung expressions of proinflammatory cytokines. Furthermore, LPS plus nanomaterials, especially with size less than 50 nm, significantly elevated circulatory levels of fibrinogen, macrophage chemoattractant protein-1, and keratinocyte-derived chemoattractant, and von Willebrand factor as compared with LPS alone. The enhancement tended overall to be greater with the smaller nanomaterials than with the larger ones. In protocol 2, latex nanomaterials with all sizes did not significantly enhance the pathophysiology of allergic asthma, characterized by eosinophilic lung inflammation and Igs production, although latex nanomaterials with less than 50 nm significantly induced/enhanced neutrophilic lung inflammation. These results suggest that latex nanomaterials differentially affect two types of (innate and adaptive immunity-dominant) lung inflammation

  17. Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and γδT-cells

    Coughlin, Beth; Schnabolk, Gloriane; Joseph, Kusumam; Raikwar, Himanshu; Kunchithapautham, Kannan; Johnson, Krista; Moore, Kristi; Wang, Yi; Rohrer, Bärbel

    2016-01-01

    Neovascular age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV). An overactive complement system is associated with AMD pathogenesis, and serum pro-inflammatory cytokines, including IL-17, are elevated in AMD patients. IL-17 is produced by complement C5a-receptor-expressing T-cells. In murine CNV, infiltrating γδT- rather than Th17-cells produce the IL-17 measurable in lesioned eyes. Here we asked whether C5a generated locally in response to CNV recruits IL-17-producing T-cells to the eye. CNV lesions were generated using laser photocoagulation and quantified by imaging; T-lymphocytes were characterized by QRT-PCR. CNV resulted in an increase in splenic IL-17-producing γδT- and Th17-cells; yet in the CNV eye, only elevated levels of γδT-cells were observed. Systemic administration of anti-C5- or anti-C5a-blocking antibodies blunted the CNV-induced production of splenic Th17- and γδT-cells, reduced CNV size and eliminated ocular γδT-cell infiltration. In ARPE-19 cell monolayers, IL-17 triggered a pro-inflammatory state; and splenocyte proliferation was elevated in response to ocular proteins. Thus, we demonstrated that CNV lesions trigger a systemic immune response, augmenting local ocular inflammation via the infiltration of IL-17-producing γδT-cells, which are presumably recruited to the eye in a C5a-dependent manner. Understanding the complexity of complement-mediated pathological mechanisms will aid in the development of an AMD treatment. PMID:27029558

  18. Inflammation meets metabolic disease: Gut feeling mediated by GLP-1

    Tamara eZietek

    2016-04-01

    Full Text Available Chronic diseases such as obesity and diabetes, cardiovascular and inflammatory bowel diseases (IBD share common features in their pathology. Metabolic disorders exhibit strong inflammatory underpinnings and vice versa, inflammation is associated with metabolic alterations. Next to cytokines and cellular stress pathways like the unfolded protein response (UPR, alterations in the enteroendocrine system are intersections of various pathologies. Enteroendocrine cells (EEC have been studied extensively for their ability to regulate gastrointestinal motility, secretion, and insulin release by release of peptide hormones. In particular the L cell-derived incretin hormone glucagon-like peptide 1 (GLP-1 has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes (T2D. Yet, accumulating data indicates a critical role for EEC and in particular for GLP-1 in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC sense the lamina propria and luminal environment including the microbiota via receptors and transporters. Subsequently mediating signals by secreting hormones and cytokines, EEC can be considered as integrators of metabolic and inflammatory signaling.This review focuses on L cell and GLP-1 functions in the context of metabolic and inflammatory diseases. The effects of incretin-based therapies on metabolism and immune system are discussed and the interrelation and common features of metabolic and immune-mediated disorders are highlighted. Moreover, it presents data on the impact of inflammation, in particular of IBD on EEC and discusses the potential role of the microbiota as link between nutrients, metabolism, immunity and disease.

  19. Inflammation Meets Metabolic Disease: Gut Feeling Mediated by GLP-1

    Zietek, Tamara; Rath, Eva

    2016-01-01

    Chronic diseases, such as obesity and diabetes, cardiovascular, and inflammatory bowel diseases (IBD) share common features in their pathology. Metabolic disorders exhibit strong inflammatory underpinnings and vice versa, inflammation is associated with metabolic alterations. Next to cytokines and cellular stress pathways, such as the unfolded protein response (UPR), alterations in the enteroendocrine system are intersections of various pathologies. Enteroendocrine cells (EEC) have been studied extensively for their ability to regulate gastrointestinal motility, secretion, and insulin release by release of peptide hormones. In particular, the L-cell-derived incretin hormone glucagon-like peptide 1 (GLP-1) has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes (T2D). Yet, accumulating data indicate a critical role for EEC and in particular for GLP-1 in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC sense the lamina propria and luminal environment, including the microbiota via receptors and transporters. Subsequently, mediating signals by secreting hormones and cytokines, EEC can be considered as integrators of metabolic and inflammatory signaling. This review focuses on L cell and GLP-1 functions in the context of metabolic and inflammatory diseases. The effects of incretin-based therapies on metabolism and immune system are discussed and the interrelation and common features of metabolic and immune-mediated disorders are highlighted. Moreover, it presents data on the impact of inflammation, in particular of IBD on EEC and discusses the potential role of the microbiota as link between nutrients, metabolism, immunity, and disease. PMID:27148273

  20. Pathogenic mechanism of second hand smoke induced inflammation and COPD

    Rahel eBirru

    2012-08-01

    Full Text Available Second hand smoke (SHS introduces thousands of toxic chemicals into the lung, including carcinogens and oxidants, which cause direct airway epithelium tissue destruction. It can also illicit indirect damage through its effect on signaling pathways related to tissue cell repair and by the abnormal induction of inflammation into the lung. After repeated exposure to second hand smoke, these symptoms can lead to the development of pulmonary inflammatory disorders, including chronic obstructive pulmonary disease (COPD. COPD is a severe pulmonary disease characterized by chronic inflammation and irreversible tissue destruction. There is no causal cure, as the mechanism behind the development and progression of the disease is still unknown. Recent discoveries implicate genetic predisposition associated with inflammatory response contributed to the development of COPD, linked to irregular innate and adaptive immunity, as well as a risk factor for cancer. The use of animal models for both cigarette smoke (CS and SHS associated in vivo experiments has been crucial in elucidating the pathogenic mechanisms and genetic components involved in inflammation related development of COPD.

  1. Web Advertisement Allocation Optimization Based on Adaptive Immune Algorithms%基于自适应免疫算法的网站广告分配优化

    闫涛; 闫继涛

    2012-01-01

    It is the key to web advertising that how to optimize its distribution to benefit both the web owner and advertisers. According to the properties of web advertisement, a hybrid pricing strategy based model is proposed. It is modeled as a constrained optimization problem to maximize the total revenue of the web. An adaptive immune algorithm is proposed to solve it. The adaptive characteristics lie in that, according to antibody affinity, antibody populations are dynamically divided into memory antibody units and general antibody units. It combines global search with local search effectively and hence improves the solution accuracy and the convergence rate. According to the characteristics of the solving problem, the relative immune operators are designed. The simulation results show that, the algorithm balances the revenues between the advertisement clients and web owners and the results are more practical.%如何优化网站广告分配,实现网站运行商和广告客户收益的双赢,是网站广告分配问题的关键.针对网站广告的特点,本文提出了一个基于混合定价策略的网站广告资源配置优化模型,将其建模为一个最大化网站总收益的约束优化问题,并通过自适应免疫克隆算法进行求解.自适应特性主要表现在:根据亲和度动态分配记忆单元和一般抗体单元,从而将全局搜索和局部搜索有效结合起来,有效提高了求解精度和收敛速度.同时,根据网站广告分配问题特点,设计了其它相关的免疫算子,如编码、克隆变异、克隆选择.仿真结果表明,算法有效平衡了网站广告客户和网站运营商的利益,求解结果更加实用.

  2. Inflammation, immunity, and vaccines for Helicobacter pylori

    D'Elios, Mario M; Andersen, Leif P

    2009-01-01

    Helicobacter pylori infects almost half of the population worldwide and represents the major cause of gastroduodenal diseases, such as duodenal and gastric ulcer, gastric adenocarcinoma, autoimmune gastritis, and B-cell lymphoma of mucosa-associated lymphoid tissue. Helicobacter pylori induces the...

  3. De novo assembly of the Indo-Pacific humpback dolphin leucocyte transcriptome to identify putative genes involved in the aquatic adaptation and immune response.

    Duan Gui

    Full Text Available BACKGROUND: The Indo-Pacific humpback dolphin (Sousa chinensis, a marine mammal species inhabited in the waters of Southeast Asia, South Africa and Australia, has attracted much attention because of the dramatic decline in population size in the past decades, which raises the concern of extinction. So far, this species is poorly characterized at molecular level due to little sequence information available in public databases. Recent advances in large-scale RNA sequencing provide an efficient approach to generate abundant sequences for functional genomic analyses in the species with un-sequenced genomes. PRINCIPAL FINDINGS: We performed a de novo assembly of the Indo-Pacific humpback dolphin leucocyte transcriptome by Illumina sequencing. 108,751 high quality sequences from 47,840,388 paired-end reads were generated, and 48,868 and 46,587 unigenes were functionally annotated by BLAST search against the NCBI non-redundant and Swiss-Prot protein databases (E-value<10(-5, respectively. In total, 16,467 unigenes were clustered into 25 functional categories by searching against the COG database, and BLAST2GO search assigned 37,976 unigenes to 61 GO terms. In addition, 36,345 unigenes were grouped into 258 KEGG pathways. We also identified 9,906 simple sequence repeats and 3,681 putative single nucleotide polymorphisms as potential molecular markers in our assembled sequences. A large number of unigenes were predicted to be involved in immune response, and many genes were predicted to be relevant to adaptive evolution and cetacean-specific traits. CONCLUSION: This study represented the first transcriptome analysis of the Indo-Pacific humpback dolphin, an endangered species. The de novo transcriptome analysis of the unique transcripts will provide valuable sequence information for discovery of new genes, characterization of gene expression, investigation of various pathways and adaptive evolution, as well as identification of genetic markers.

  4. Bioactive Egg Components and Inflammation

    Catherine J. Andersen

    2015-09-01

    Full Text Available Inflammation is a normal acute response of the immune system to pathogens and tissue injury. However, chronic inflammation is known to play a significant role in the pathophysiology of numerous chronic diseases, such as cardiovascular disease, type 2 diabetes mellitus, and cancer. Thus, the impact of dietary factors on inflammation may provide key insight into mitigating chronic disease risk. Eggs are recognized as a functional food that contain a variety of bioactive compounds that can influence pro- and anti-inflammatory pathways. Interestingly, the effects of egg consumption on inflammation varies across different populations, including those that are classified as healthy, overweight, metabolic syndrome, and type 2 diabetic. The following review will discuss the pro- and anti-inflammatory properties of egg components, with a focus on egg phospholipids, cholesterol, the carotenoids lutein and zeaxanthin, and bioactive proteins. The effects of egg consumption of inflammation across human populations will additionally be presented. Together, these findings have implications for population-specific dietary recommendations and chronic disease risk.

  5. Inflammation and Heart Disease

    ... Pressure High Blood Pressure Tools & Resources Stroke More Inflammation and Heart Disease Updated:Apr 18,2016 Understand the risks of inflammation. Although it is not proven that inflammation causes ...

  6. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome

    Lessard, Christopher J.; Li, He; Adrianto, Indra; Ice, John A.; Rasmussen, Astrid; Grundahl, Kiely M.; Kelly, Jennifer A.; Dozmorov, Mikhail G.; Miceli-Richard, Corinne; Bowman, Simon; Lester, Sue; Eriksson, Per; Eloranta, Maija-Leena; Brun, Johan G.; Gøransson, Lasse G.; Harboe, Erna; Guthridge, Joel M.; Kaufman, Kenneth M.; Kvarnström, Marika; Jazebi, Helmi; Graham, Deborah S. Cunninghame; Grandits, Martha E.; Nazmul-Hossain, Abu N. M.; Patel, Ketan; Adler, Adam J.; Maier-Moore, Jacen S.; Farris, A. Darise; Brennan, Michael T.; Lessard, James A.; Chodosh, James; Gopalakrishnan, Rajaram; Hefner, Kimberly S.; Houston, Glen D.; Huang, Andrew J.W.; Hughes, Pamela J.; Lewis, David M.; Radfar, Lida; Rohrer, Michael D.; Stone, Donald U.; Wren, Jonathan D.; Vyse, Timothy J.; Gaffney, Patrick M.; James, Judith A.; Omdal, Roald; Wahren-Herlenius, Marie; Illei, Gabor G.; Witte, Torsten; Jonsson, Roland; Rischmueller, Maureen; Rönnblom, Lars; Nordmark, Gunnel; Ng, Wan-Fai; Mariette, Xavier; Anaya, Juan-Manuel; Rhodus, Nelson L.; Segal, Barbara M.; Scofield, R. Hal; Montgomery, Courtney G.; Harley, John B.; Sivils, Kathy L. Moser

    2013-01-01

    Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome. PMID:24097067

  7. Null steering of adaptive beamforming using linear constraint minimum variance assisted by particle swarm optimization, dynamic mutated artificial immune system, and gravitational search algorithm.

    Darzi, Soodabeh; Kiong, Tiong Sieh; Islam, Mohammad Tariqul; Ismail, Mahamod; Kibria, Salehin; Salem, Balasem

    2014-01-01

    Linear constraint minimum variance (LCMV) is one of the adaptive beamforming techniques that is commonly applied to cancel interfering signals and steer or produce a strong beam to the desired signal through its computed weight vectors. However, weights computed by LCMV usually are not able to form the radiation beam towards the target user precisely and not good enough to reduce the interference by placing null at the interference sources. It is difficult to improve and optimize the LCMV beamforming technique through conventional empirical approach. To provide a solution to this problem, artificial intelligence (AI) technique is explored in order to enhance the LCMV beamforming ability. In this paper, particle swarm optimization (PSO), dynamic mutated artificial immune system (DM-AIS), and gravitational search algorithm (GSA) are incorporated into the existing LCMV technique in order to improve the weights of LCMV. The simulation result demonstrates that received signal to interference and noise ratio (SINR) of target user can be significantly improved by the integration of PSO, DM-AIS, and GSA in LCMV through the suppression of interference in undesired direction. Furthermore, the proposed GSA can be applied as a more effective technique in LCMV beamforming optimization as compared to the PSO technique. The algorithms were implemented using Matlab program. PMID:25147859

  8. RED for PMTCT: an adaptation of immunization's Reaching Every District approach increases coverage, access, and utilization of PMTCT care in Bondo District, Kenya.

    Kanyuuru, Lynn; Kabue, Mark; Ashengo, Tigistu A; Ruparelia, Chandrakant; Mokaya, Evans; Malonza, Isaac

    2015-06-01

    Gaps exist in coverage, early access, and utilization of prevention of mother-to-child transmission of HIV (PMTCT) services in Kenya. The Maternal and Child Health Integrated Program, led by Jhpiego, piloted an adaptation of immunization's Reaching Every District (RED) approach in Bondo District as a way of improving PMTCT care. Routine district-level monthly summary service delivery pre- and post-implementation data were analyzed. Marked improvements resulted in the proportion of HIV-infected and non-infected pregnant women completing four focused prenatal care visits, from 25% to 41%, and the proportion of HIV-exposed infants (HEIs) tested at six weeks, from 27% to 78% (PHIV infection at 12months was 52%, while 77% of HEIs were issued antiretroviral prophylaxis by the end of the pilot. Implementation of RED for PMTCT demonstrated that PMTCT services can be delivered effectively in the context of the existing community strategy and resulted in increased coverage, access, and utilization of care for HIV-positive pregnant women and their children. PMID:26115861

  9. Asthma: the importance of dysregulated barrier immunity.

    Lambrecht, Bart N; Hammad, Hamida

    2013-12-01

    Chronic asthma is an inflammatory disease of the airway wall that leads to bronchial smooth muscle hyperreactivity and airway obstruction, caused by inflammation, goblet cell metaplasia, and airway wall remodeling. In response to allergen presentation by airway DCs, T-helper lymphocytes of the adaptive immune system control many aspects of the disease through secretion of IL-4, IL-5, IL-13, IL-17, and IL-22, and these are counterbalanced by cytokines produced by Treg cells. Many cells of the innate immune system such as mast cells, basophils, neutrophils, eosinophils, and innate lymphoid cells also play an important role in disease pathogenesis. Barrier epithelial cells are being ever more implicated in disease pathogenesis than previously thought, as these cells have in recent years been shown to sense exposure to allergens via pattern recognition receptors and to activate conventional and inflammatory-type DCs and other innate immune cells through the secretion of thymic stromal lymphopoietin, granulocyte-macrophage colony stimulating factor, IL-1, IL-33, and IL-25. Understanding this cytokine crosstalk between barrier epithelial cells, DCs, and immune cells provides important insights into the mechanisms of allergic sensitization and asthma progression as discussed in this review. PMID:24165907

  10. T cells are necessary for ILC2 activation in house dust mite-induced allergic airway inflammation in mice.

    Li, Bobby W S; de Bruijn, Marjolein J W; Tindemans, Irma; Lukkes, Melanie; KleinJan, Alex; Hoogsteden, Henk C; Hendriks, Rudi W

    2016-06-01

    Allergic asthma is a chronic inflammation of the airways mediated by an adaptive type 2 immune response. Upon allergen exposure, group 2 innate lymphoid cells (ILC2s) can be rapidly activated and represent an early innate source of IL-5 and IL-13. Here, we used a house dust mite (HDM)-driven asthma mouse model to study the induction of ILC2s in allergic airway inflammation. In BALF, lungs, and lymph nodes, ILC2 activation is critically dependent on prior sensitization with HDM. Importantly, T cells are required for ILC2 induction, whereby T-cell activation precedes ILC2 induction. During HDM-driven allergic airway inflammation the accumulation of ILC2s in BALF is IL-33 independent, although infiltrating ILC2s produce less cytokines in Il33(-/-) mice. Transfer of in vitro polarized OVA-specific OT-II Th2 cells alone or in combination with Th17 cells followed by OVA and HDM challenge is not sufficient to induce ILC2, despite significant eosinophilic inflammation and T-cell activation. In this asthma model, ILC2s are therefore not an early source of Th2 cytokines, but rather contribute to type 2 inflammation in which Th2 cells play a key role. Taken together, ILC2 induction in HDM-mediated allergic airway inflammation in mice critically depends on activation of T cells. PMID:27062360

  11. Towards a Conceptual Framework for Innate Immunity

    Twycross, Jamie

    2010-01-01

    Innate immunity now occupies a central role in immunology. However, artificial immune system models have largely been inspired by adaptive not innate immunity. This paper reviews the biological principles and properties of innate immunity and, adopting a conceptual framework, asks how these can be incorporated into artificial models. The aim is to outline a meta-framework for models of innate immunity.

  12. Adaptation to High Grain Diets Proceeds Through Minimal Immune System Stimulation and Differences in Extracellular Matrix Protein Expression in A Model of Subacute Ruminal Acidosis in Non-lactating Dairy Cows

    L. Dionissopoulos

    2012-01-01

    Full Text Available Problem statement: Subacute Ruminal Acidosis (SARA is a metabolic disorder affecting approximately 20% of all dairy cattle in North America. Although the presence of SARA has been described for some time, the etiology of the disorder remains uncertain. For example, many animals diagnosed with SARA seem to remodel and adapt their epithelium to accommodate the stresses imposed by SARA, but not before exacting a significant health and economic toll. Specifically, a search is on in which a desire to identify the system and associated pathways that are causative agents in the progression and development of SARA is evident. We hypothesize that adaptation to SARA is facilitated by the immune system. Approach: In order to answer of this question, 4 mature, non-lactating dairy cattle were transitioned from a High Fiber (HF; 0% grain diet to High Grain (HG; 65% grain diet. Having fed the HG diet for three weeks, the cattle were then transitioned back to the HF diet for an additional three weeks to facilitate adaptation. SARA was diagnosed by pH data only during the first week and not during the remaining weeks, indicating that adaptation to the HG diet took place within one week. Results: In this study, significant (pConclusion: These results indicate that the immune system is involved in the adaptation of the rumen epithelium to a HG diet, but to a lesser extent than was previously thought. This is the first time an attempt has been made to link the immune system and wound healing in the adaptation of the bovine rumen to a HG diet."""

  13. Impact of inflammation on vascular disease in hypertension.

    Virdis, Agostino; Dell'Agnello, Umberto; Taddei, Stefano

    2014-07-01

    Low grade inflammation exerts a crucial pathogenic role in hypertension and cardiovascular disease. A large body of evidence indicates that innate and adaptive immune systems, and in particular T cells, are involved. A balance between T-effector lymphocytes and Treg lymphocytes represents a crucial regulatory mechanism that, when altered, favours blood pressure elevation and organ damage development. Of note, Treg lymphocytes exert important anti-inflammatory properties, whose activities guarantees vascular homeostasis and protects the vessel wall from the development of atherosclerosis. In humans, most of evidence ascertaining essential hypertension as a condition of chronic low-grade inflammatory status revealed a strict and independent association between CRP, TNF-α, IL-6 or adhesion molecules and vascular changes in essential hypertensive patients. Evidence of involvement of the immune system in vasculature from patients with hypertension or cardiovascular disease starts to appear in literature. Further investigation on immunity, including the role of T-lymphocytes, will help develop of new therapeutic targets that may improve outcomes in hypertension and cardiovascular disease and discover novel approaches in the treatment of hypertension and vascular disease. PMID:24846805

  14. Surfactant and allergic airway inflammation.

    Winkler, Carla; Hohlfeld, Jens M

    2013-01-01

    Pulmonary surfactant is a complex mixture of unique proteins and lipids that covers the airway lumen. Surfactant prevents alveolar collapse and maintains airway patency by reducing surface tension at the air-liquid interface. Furthermore, it provides a defence against antigen uptake by binding foreign particles and enhancing cellular immune responses. Allergic asthma is associated with chronic airway inflammation and presents with episodes of airway narrowing. The pulmonary inflammation and bronchoconstriction can be triggered by exposure to allergens or pathogens present in the inhaled air. Pulmonary surfactant has the potential to interact with various immune cells which orchestrate allergen- or pathogen-driven episodes of airway inflammation. The complex nature of surfactant allows multiple sites of interaction, but also makes it susceptible to external alterations, which potentially impair its function. This duality of modulating airway physiology and immunology during inflammatory conditions, while at the same time being prone to alterations accompanied by restricted function, has stimulated numerous studies in recent decades, which are reviewed in this article. PMID:23896983

  15. Allergies and Asthma: Do Atopic Disorders Result from Inadequate Immune Homeostasis arising from Infant Gut Dysbiosis?

    Johnson, Christine C; Ownby, Dennis R

    2016-04-01

    Our global hypothesis is that atopic conditions and asthma develop because an individual's immune system is not able to appropriately resolve inflammation resulting from allergen exposures. We propose that the failure to appropriately down-regulate inflammation and produce a toleragenic state results primarily from less robust immune homeostatic processes rather than from a tendency to over-respond to allergenic stimuli. An individual with lower immune homeostatic capacity is unable to rapidly and completely terminate, on average over time, immune responses to innocuous allergens, increasing risk of allergic disease. A lack of robust homeostasis also increases the risk of other inflammatory conditions, such as prolonged respiratory viral infections and obesity, leading to the common co-occurrence of these conditions. Further, we posit that the development of vigorous immune homeostatic mechanisms is an evolutionary adaptation strongly influenced by both 1) exposure to a diverse maternal microbiota through the prenatal period, labor and delivery, and, 2) an orderly assemblage process of the infant's gut microbiota ecosystem shaped by breastfeeding and early exposure to a wide variety of ingested foods and environmental microbes. This early succession of microbial communities together with early allergen exposures orchestrate the development of an immune system with a robust ability to optimally control inflammatory responses and a lowered risk for atopic disorders. PMID:26776722

  16. Early environments and the ecology of inflammation.

    McDade, Thomas W

    2012-10-16

    Recent research has implicated inflammatory processes in the pathophysiology of a wide range of chronic degenerative diseases, although inflammation has long been recognized as a critical line of defense against infectious disease. However, current scientific understandings of the links between chronic low-grade inflammation and diseases of aging are based primarily on research in high-income nations with low levels of infectious disease and high levels of overweight/obesity. From a comparative and historical point of view, this epidemiological situation is relatively unique, and it may not capture the full range of ecological variation necessary to understand the processes that shape the development of inflammatory phenotypes. The human immune system is characterized by substantial developmental plasticity, and a comparative, developmental, ecological framework is proposed to cast light on the complex associations among early environments, regulation of inflammation, and disease. Recent studies in the Philippines and lowland Ecuador reveal low levels of chronic inflammation, despite higher burdens of infectious disease, and point to nutritional and microbial exposures in infancy as important determinants of inflammation in adulthood. By shaping the regulation of inflammation, early environments moderate responses to inflammatory stimuli later in life, with implications for the association between inflammation and chronic diseases. Attention to the eco-logics of inflammation may point to promising directions for future research, enriching our understanding of this important physiological system and informing approaches to the prevention and treatment of disease. PMID:23045646

  17. Intelligent direct analysis of physical and mechanical parameters of tunnel surrounding rock based on adaptive immunity algorithm and BP neural network

    Xiao-rui Wang; Yuan-han Wang; Xiao-feng Jia

    2009-01-01

    Because of complexity and non-predictability of the tunnel surrounding rock, the problem with the determination of the physical and, mechanical parameters of the surrounding rock has become a main obstacle to theoretical research and numerical analysis in tunnel engineering. During design, it is a frequent practice, therefore, to give recommended values by analog based on experience. It is a key point in current research to make use of the displacement back analytic method to comparatively accurately determine the parameters of the surrounding rock whereas artificial intelligence possesses an exceptionally strong capability of identifying, expressing and coping with such complex non-linear relationships. The parameters can be verified by searching the optimal network structure, using back analysis on measured data to search optimal parameters and performing direct computation of the obtained results. In the current paper, the direct analysis is performed with the biological emulation system and the software of Fast Lagrangian Analysis of Continua (FLAC3D. The high non-linearity, network reasoning and coupling ability of the neural network are employed. The output vector required of the training of the neural network is obtained with the numerical analysis software. And the overall space search is conducted by employing the Adaptive Immunity Algorithm. As a result, we are able to avoid the shortcoming that multiple parameters and optimized parameters are easy to fall into a local extremum. At the same time, the computing speed and efficiency are increased as well. Further, in the paper satisfactory conclusions are arrived at through the intelligent direct-back analysis on the monitored and measured data at the Erdaoya tunneling project. The results show that the physical and mechanical parameters obtained by the intelligent direct-back analysis proposed in the current paper have effectively unproved the recommended values in the original prospecting data. This is of

  18. Unraveling the Complex Relationship Triad between Lipids, Obesity, and Inflammation

    Khan, Shahida A.; Ashraf Ali; Khan, Sarah A.; Solafa A. Zahran; Ghazi Damanhouri; Esam Azhar; Ishtiaq Qadri

    2014-01-01

    Obesity today stands at the intersection between inflammation and metabolic disorders causing an aberration of immune activity, and resulting in increased risk for diabetes, atherosclerosis, fatty liver, and pulmonary inflammation to name a few. Increases in mortality and morbidity in obesity related inflammation have initiated studies to explore different lipid mediated molecular pathways of attempting resolution that uncover newer therapeutic opportunities of anti-inflammatory components. M...

  19. Eosinophilic inflammation in allergic asthma

    Samantha Souza Possa

    2013-04-01

    Full Text Available Eosinophils are circulating granulocytes involved in pathogenesis of asthma. A cascade of processes directed by Th2 cytokine producing T-cells influence the recruitment of eosinophils into the lungs. Furthermore, multiple elements including interleukin (IL-5, IL-13, chemoattractants such as eotaxin, Clara cells, and CC chemokine receptor (CCR3 are already directly involved in recruiting eosinophils to the lung during allergic inflammation. Once recruited, eosinophils participate in the modulation of immune response, induction of airway hyperresponsiveness and remodeling, characteristic features of asthma. Various types of promising treatments for reducing asthmatic response are related to reduction in eosinophil counts both in human and experimental models of pulmonary allergic inflammation, showing that the recruitment of these cells really plays an important role in the pathophysiology of allergic diseases such asthma.

  20. Comparative immune systems in animals.

    Yuan, Shaochun; Tao, Xin; Huang, Shengfeng; Chen, Shangwu; Xu, Anlong

    2014-02-01

    Animal immune systems can be classified into those of innate immunity and those of adaptive immunity. It is generally thought that the former are universal for all animals and depend on germline-encoded receptors that recognize highly conserved pathogen-associated molecular patterns (PAMPs), whereas the latter are vertebrate specific and are mediated primarily by lymphocytes bearing a unique antigen receptor. However, novel adaptive or adaptive-like immunities have been found in invertebrates and jawless vertebrates, and extraordinarily complex innate immunities, created through huge expansions of many innate gene families, have recently been found in the cephalochordate amphioxus and the echinoderm sea urchin. These studies not only inspire immunologists to seek novel immune mechanisms in invertebrates but also raise questions about the origin and evolution of vertebrate immunities. PMID:25384142