We performed a subanalysis of a cross-sectional study (EO code: EO-07–024) to analyze the role of thymic output and immune activation in 230 patients who were attended in our HIV Outpatient Unit while receiving antiretroviral therapy and had sustained viral suppression for at least 2 years. Discordant patients were defined as individuals with a CD4 cell count al- ways below 350 cells/µL; concordant patients were defined as individuals with a CD4 cell count above 400 cells/µL 8 . The study was approved by the Institu-
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Other findings in our study may help explain the effect on the latent reservoir. Unexpectedly, 2LTR DNA circles were transient- ly detectable during MVC intensification. Due to its mechanism of action, MVC is not expected to increase 2LTR DNA circles, even when inhibiting persistent viral replication. The increase in levels of this marker suggests that treatment with MVC in patients with undetectable viral load may induce viral replication. Preclinical studies showed that MVC had no agonistic activity on activated CD4 + T cells and, therefore, could not induce viral replication . Later reports, however, have shown that the possibility of acting as a partial agonist on CCR5 could be dependent on cell type . Therefore, MVC could activate CCR5 in resting CD4 + T cells and, through intracellular signalling, increase transcrip- tional activation of the latent virus. As an alternative hypothesis, CCR5 blockade by MVC could lead natural ligands or chemokines to bind to other receptors and induce latent HIV transcriptional activation through distinct signalling pathways. Both hypotheses would be consistent with the reduced number of latently infected memory T cells found in this study, the transient increase in the number of copies of HIV RNA seen in some patients, and the increased bacterial translocation plus migration of a4b7 cells to the gut. This possibility is further supported by the increased immune activation in intestinal tissue biopsies that was observed in another MVC intensification study . Finally, trafficking of cells to peripheral blood from some other compartment cannot be discarded to explain some of the results, including the increase in 2 LTR circles.
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PLWH under suppressive HAART. Overall, we hypothesized that despite HAART-induced viral suppression, PLWH have alterations in these parameters, compared with healthy controls. Certainly, despite treatment, PLWH had a decreased function of activated Tc17 cells and a low Tc17/Tc1 cells ratio compared with HIV-seronegative healthy volunteers, that correlated with high cellular and plasma immune activation levels. This dysfunction was particularly associated with the expression of CD38 and the programmed death 1 protein (PD-1). A potential beneficial effect of SSZ in the restoration of these subsets was observed. The Tc17 response is proposed as a novel cellular correlate of systemic immune activation in PLWH under HAART, as well as a potential target for the improvement of immune reconstitution in these individuals.
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Abstract: The aims of the study were to assess the usefulness of expression macroarrays to determine the pattern of expression of cytokines, chemokines and molecules related to immune system activation pathways, in non-stimulated intact intestinal tissue specimens from patients with active CD (aCD) and on a gluten-free diet (GFD), to compare it with two groups of controls with either normal or altered mucosal architecture, and to establish putative targets for diagnostic markers or therapeutic intervention. We have experienced the lack of sensitivity to detect signal of genes with low level of expression. In spite of that, active CD seems to show a Th1 cytokine pattern, but with signs of Th2 activity. Cytokines such as IL-9, IL-11, IL-21 or MIF might be involved in mucosal infl ammation in CD. In GFD, some memory cells and DC’s activity remains, and factors that maintain this remnant activation might be responsible of the fast mucosal response on gluten chal- lenge. STAT3 and STAT5 pathways, and their regulatory molecules SOCS’s may result keys for understanding mucosal infl ammation in gut and putative targets for further research.
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such as Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), Nod-like receptors (NLRs), AIM2-like receptors (ALRs), C-type lectin receptors (CLRs) and other DNA sensors, recognize invariant molecular structures called pathogen-associated molecular patterns (PAMPs) (e.g., Lipopolysaccharide -LPS-, peptidoglycan, unmethylated CpG- DNA, bacterial lipoprotein, and yeast mannans) that are shared by numerous pathogens, but are not normally expressed in host tissues [1, 4]. TLRs are type I transmembrane glycoproteins that play a key role in the immune response against microbes. TLRs are expressed in various immune cells including macrophages, monocytes, neutrophils, mast cells, eosinophils, DCs, and T cells. Ten human TLRs have been identified to date and are localized on the cell surface such as the case of TLRs 1, 2, 4, 5, 6, 10 or have an endosomal location as TLRs 3, 7, 8, 9. Important TLRs expressed on myeloid cells are TLR4 that recognizes LPS through association with soluble protein MD-2, and endosomal TLR7/9 that recognize viral single stranded RNA (ssRNA) [3, 5]. On pathogen invasion, PRRs trigger the activation of NF-κB, type I interferon (IFN), or other inflammasome signaling pathways on myeloid cells, such as DCs or macrophages. In turn, this leads to the production of a variety of pro- inflammatory and antiviral cytokines and chemokines, as well as the maturation and migration of antigen-presenting cells (APCs), such as DCs, macrophages and monocytes. The activation of APCs is a prerequisite for the induction of adaptive immunity .
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Several studies have suggested the occurrence of large immu- nity costs through trade-offs between immunocompetence and life history traits (Barnes and Siva-Jothy, 2000; Armitage et al., 2003; Fedorka et al., 2004; Gwynn et al., 2005; Rantala and Roff, 2005; Springate and Thomas, 2005). However, a direct cost of the im- mune response on metabolic rate has been difﬁcult to demonstrate (for invertebrates see Freitak et al., 2003 and for vertebrates Malvin and Kluger, 1979; Demas et al., 1997; Svensson et al., 1998; Lochmiller and Deerenberg, 2000; Moreno et al., 2001). The predic- tion of the outcome of the pathogen–host interaction under vari- ous natural and human-induced environmental conditions would require the measurement of immunocompetence and costs of im- mune traits. In this study we have assessed the question as to whether the environmental temperature can modulate the im- mune response in insects. Further, we explored a possible depen- dence for energetic cost on both, the immune response and the environmental temperature. We hypothesised that warmer tem- peratures increase the immune activation, in parallel with an in- crease in metabolic rate and loss of body mass.
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regulator of vasotone, and its hemostatic function. The destruction of the glycocalyx results, among many other effects, in the exposure of adhesion molecules, resulting in the trapping (selectins) and transmigration (integrins) of activated leukocytes, activation of hemostatic compounds in favor of a proprocoagulant state, and the loss of mechanotransducer function due to these molecules, losing their natural environment essential for the sensing of sheer stress. The barrier function of the ECL is compromised by direct membrane destruction due to lipid peroxidation induced by ROS/RNS, as well as the decomposition of molecules such as tight junctions anchoring the EC together. The role of the EC as a vasomotor tone regular is lost due to the loss of function of the mechanotransducer system, the overproduction of iNOS-mediated NO, and the loss of transcellular gap junction essential for an integrative control of vasotone along the ECL. Endothelial destruction also results in the release of microparticles contributing to the pathogenic effect of EC dysfunction. Source: Acute Dialysis Quality Initiative 14, www.ADQI.net 2014; used with permission. iNOS indicates inducible nitric oxide synthase; RNS, reactive nitrogen species.
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A 57-year-old male originally from Nigeria presented with a 2-week history of right upper quadrant abdominal pain, nausea, fatigue and confusion. Medical history was significant for a recent diagnosis of HIV/HBV co-infec- tion 2 months prior, identified when he presented with ataxia attributed to neurotoxoplasmosis. At that time, labs were notable for low CD4 count, positive HIV and HBV viral loads, and normal AST/ALT consistent with AIDS and immune tolerant, chronic HBV (Table 1). Hepatitis C antibody was negative. He was treated for Toxoplasmosis with pyrimethamine, leucovorin and clindamycin as well as initiated on HAART with emtricitabine, tenofovir and reltegravir. Sulfamethoxazole-trimethoprim was also start- ed for pneumocystis jiroveci pneumonia prophylaxis. He remained on therapy for 2 months without incident; with outpatient, labs showing normal aminotransferases at 1 month of therapy.
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amyotrophic lateral sclerosis (16). TZDs have been proposed as potential therapeutic agents for both AD and multiple sclerosis (17), and most of their neuroprotective effects are ascribed to either improved insulin sensitivity, or to their anti-inflamma- tory action through PPAR␥ activation in glial cells (18, 19). However, activation of PPAR␥ by three different TZDs pro- tected rat hippocampal neurons against ␤-amyloid (A␤)-in- duced damage (20), and the TZD rosiglitazone protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity (21). In addition, PPAR ␥ activation by rosiglita- zone up-regulates the Bcl-2 protective pathway and prevents neuronal degeneration induced by both oxidative stress and treatment with A␤ fibrils, with a concomitant increase in mito- chondrial viability (22). Recent studies have also provided evi- dence that the expression of PGC-1␣, a potent co-activator of PPAR ␥ , is repressed by mutant huntingtin expression, and when PGC-1 ␣ knock-out (KO) mice are crossed with HD knockin mice, this resulted in increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice (2). At the same time, there is evidence suggesting that PPAR␥ ago- nists are neuroprotective and increase mitochondrial function (23, 24). It was also demonstrated that oral treatment with ros- iglitazone induced mitochondrial biogenesis in mouse brain (25). Therefore, in this study, we explored the possibility of using PPAR␥ activation to ameliorate mutant huntingtin-in- duced mitochondrial dysfunction (5, 6, 26). Our results indicate that there are significant defects in the PPAR␥ signaling path- way in mutant huntingtin-expressing cells in comparison with cells that express wild-type huntingtin protein. In addition, pre- treatment of mutant huntingtin-expressing cells with the PPAR␥ agonist rosiglitazone prevented the loss of mitochon- drial potential, mitochondrial calcium deregulation, and oxida- tive stress overproduction in response to intracellular calcium overload. These findings suggest that activation of the PPAR␥ signaling pathway could ameliorate the mitochondrial function deficits that occur in HD.
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Herpes simplex viruses and humans have co-existed for tens of thousands of years. This long relationship has translated into the evolution and selection of viral determinants to evade the host immune response and reciprocally the evolution and selection of host immune components for limiting virus infection and damage. Currently there are no vaccines available to avoid infection with these viruses or therapies to cure them. Herpes simplex viruses are neurotropic and reside latently in neurons at the trigeminal and dorsal root ganglia, occasionally reactivating. Most viral recurrences are subclinical and thus, unnoticed. Here, we discuss the initial steps of infection by herpes simplex viruses and the molecular mechanisms they have developed to evade innate and adaptive immunity. A better understanding of the molecular mechanisms evolved by these viruses to evade host immunity should help us envision novel vaccine strategies and therapies that limit infection and dissemination.
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Abstract Primary immune thrombocytopenia, formerly known as immune thrombocytopenic purpura, is a disease for which the clinical and therapeutic management has always been contro- versial. The ITP working group of the Spanish Society of Paediatric Haematology and Oncology has updated its guidelines for diagnosis and treatment of primary immune thrombocytope- nia in children, based on current guidelines, bibliographic review, clinical assays, and member consensus. The main objective is to reduce clinical variability in diagnostic and therapeutic pro- cedures, in order to obtain best clinical results with minimal adverse events and good quality of life.
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Two different ceramic waste materials were used for the alkaline activation process: red clay brick (B) and porcelain stoneware (P). The materials were crushed in a jaw crusher to obtain a particle diameter of less than 4 mm. This granulated material was then ground in a laboratory-type ball mill (alumina medium, 40 min). Particle size distribution was measured using a laser analyzer (Mastersizer 2000, Malvern Instruments). Figure 1 presents both cumulative curves. As shown, both powders presented a similar particle distribution, with particles ranging from 0.2 to 100 µm, 90% in volume under 50 µm, and almost 7% had a diameter under 1 µm. Despite both ceramic materials having a mean particle diameter close to 20 microns, a slightly larger amount of thinner particles (under 10 micron) was observed in the red clay brick powder.
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The glucocorticoid cortisol and its synthetic analog dexa- methasone are potent modulators of the immune system with immunosuppressive effects (12). We recently showed that there are no changes in salivary cortisol levels after awaken- ing, during the day, or after the dexamethasone suppression test (DST) in a clinical burnout group compared with a healthy control group (15). Irrespective of whether the negative find- ings could be replicated in the present sample, we considered it worthwhile to measure cortisol parameters again to inves- tigate their potential role in the immune function. The DST is an indication for glucocorticoid receptor sensitivity and subsequent negative feedback functioning of the hypothalamic– pituitary–adrenal axis (16). The steroid dehydroepiandros- terone-sulfate (DHEAS) also shows an immunomodulatory function but opposite from cortisol (17). Low DHEAS levels seem to be associated with poorer health (18), although Grossi et al. and Moch et al. found no differences in serum or plasma DHEAS in participants with burnout (19,20). A shift in the cortisol/DHEA(S) ratio toward cortisol has been associated with mood disorders and perceived stress (21).
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A number of studies support the immunoregulatory action of melatonin on innate immunity. Melatonin stimulates the production of progenitor cells for granulocytes and macrophages (GM-CFU) and has a general stimulatory action on hemopoiesis . Melatonin receptors are detectable in monocyte/macrophage lineage and melatonin binding to both membrane and nuclear receptors stimulates the production of GM-CFU cells . Exogenous melatonin augments NK cells and monocytes in both the bone marrow and the spleen with a latency of 7 to 14 days. The action of melatonin on monocyte production can be partly due to its direct action on melatonin receptors or may be due to an increase of monocyte sensitivity to stimulants like IL-3, IL- 4, IL-6 or GM-colony stimulating factor (GM-CSF) . Melatonin increases the actual production of GM-CSF cell lineage but not the inter-organ trafficking of myeloid precursors . An increased activation of monocytes/macrophages by melatonin has also been reported in another study in rodents . As both macrophage cells and neutrophils form important components of the innate immune system, the stimulatory action of melatonin reflects a significant immunoenhancing property.
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The untargeted metabolomics study of the serum showed significant changes in the profile of parasitized fish and the PLS-DA clearly separated parasitized fish from control ones into different clusters, confirming the stability and reproducibility of the LC-MS analysis. In previous studies, we have shown that this approach can detect differences in dietary interventions and the nutri- tional status of GSB [25, 26]. Metabolomics have been applied recently in several areas of aquaculture , including infectious fish diseases . However, its appli- cation in fish parasitic diseases is very scarce, and only done thus far in naturally infected fish. In one of the few studies, in Coilia nasus, from the 391 annotated com- pounds, 65 metabolites were significantly regulated in Anisakid-infected groups, and the multivariate analyses of the serum metabolite profiles showed good separa- tion between infected and non-infected samples , as in the present study. In a GC/MS study of a very similar enteric myxozoan disease, the PLS-DA of 53 metabolites showed three distinct groups according to their parasite load . In E. leei-infected sera, the regulated metabo- lites were involved mainly in amino acid catabolism, fatty acid oxidation, nucleoside, lysophospholipid, vitamin and polyphenol metabolism. Similarly, in the above men- tioned cases, the main pathways affected by the para- sitic infection were amino acids and fatty acids  and amino acids, nucleotide derivatives, phospholipids, and immune-related metabolites .
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7Ke tKerapeutic bene¿t reported from allogeneic stem cell transplantation is attributed to tKe graft versus tumor effect produced by tKe infused donor immune effector cells to eradicate tumor cells. However, the immune response produced by the donor immune effector cells is not speci¿c creating not only the graft versus tumor effect, but also the detrimental effects of graft versus host disease. Recent reports have shown that the infusion of collected ³bystander´ lymphocytes from the stem cell autograft correlates with lymphocyte recovery and clinical outcomes in patients undergoing autologous stem cell transplantation (ASCT), similar to the graft versus tumor effect seen in the allogeneic stem cell transplantation without the adverse effects of graft versus host disease. The discovery that host immune effector cells collected at the same time as the stem cells can improve clinical outcomes post-ASCT, suggest that autograft can be viewed not only as a therapeutic maneuver to recover bone marrow function after deliver high-dose chemotherapy, but also as an adoptive immunotherapeutic intervention capable of eradicating tumor cells in cancer patients. In this article, we review how to enhance host immune effector cells collection, the different immune effector cells collected and infused from the stem cell autograft, and their association with clinical outcome post-ASCT. Key words: Graft versus tumor effect, stem cell.
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Background: The immune system is a complex network of cells and molecules that play a relevant role in the defence against infections through its ability to recognize and develop a response against non-self antigens. Although the inflammatory response is essential for maintaining tissue homeostasis, protecting against infection and mediating immune responses, it can also contribute to tissue injury. In fact, the immune system is abnormally activated at the systemic level in patients and experimental models with cirrhosis and ascites contributing to the progression of the disease. Immunitary cells become activated after interacting at the mesenteric lymph nodes (MLN) with bacteria translocated from the gut, and thereafter reach the bloodstream by recirculation. The alteration is characterized by expansion of activated lymphocytes and monocytes in peripheral blood and an increased production of proinflammatory cytokines. Despite the pivotal role of systemic activation of the immune system in cirrhosis, it is unknown if this abnormality already exists in the compensated pre-ascitic stage of the disease. It is possible to hypothesize that the liver, the main organ of inflammation in cirrhosis, has a crucial role as a source of abnormally activated monocytes and lymphocytes.
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T cell response, skewing cytokine responses towards a Th1 phenotype in mice . These data are in agreement with the observation of the leptin eﬀect on anti-CD3 stimulation of T cells, which increases the production of the proinflammatory cytokine IFN-γ . The eﬀect of leptin polarizing T cells towards a Th1 response seems to be mediated by stimulating the synthesis of IL-2, IL-12, and IFN-gamma and the inhibition of the production of IL-10 and IL-4 [36, 62]. Th1 polarization has been correlated with hyperleptinemia in hemodialysis patients  and the protection of ob/ob mice in Th1- as well as in Th2-dependent inflammation is provided by a decreased expression of the key transcription factors for Th1 and Th2 polarization, T-bet and GATA-3 in naive ob/ob T cells. In this case, leptin was found to be necessary in T-helper 1- (Th1-) dependent inflammatory processes acting as a critical regulator of CD4+ T cell polarization in vitro and in vivo . These data regarding leptin modulation of Th1-type cytokine production are in line with the observed eﬀects of leptin stimulating TNF-α and IL-6 production by monocytes , further suggesting the possible role of human leptin in the regulation of the immune system inducing a proinflammatory response. On peripheral blood mononuclear cells of patients with ankylosing spondylitis, leptin exerts proinflammatory eﬀect  as well as it enhances the proinflammatory cytokines in normal colonocytes and in HT29 xenografted tumor colono- cytes. Colonocyte-derived products after leptin treatment stimulated perforin and granzyme B expressions in normal CD8 (+) T cells in vitro . In addition, leptin alone or in combination with IL-1 enhanced the expression of iNOS and COX-2 and production of NO, PGE (2), IL-6, and IL- 8. The e ﬀ ects of leptin are mediated through activation of transcription factor nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathway c-Jun NH (2)-terminal kinase (JNK).The increased synthesis of proinflammatory mediators is mediated by nitric oxide (NO) in human osteoarthritic cartilage .
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MEK1 and MEK2 kinase (MAP kinase kinases) are phosphor- ylated after BCR engagement on two serine residues at positions 217 and 221 by Raf. MEK then activates p44 and p42 ERK1/2 MAP kinases by phosphorylating both threonine and tyrosine residues at sites within the activation loop. Using a phospho- MEK1/2 (Ser217/221)–specific antibody, we studied 11 CLL patients and detected constitutively phosphorylated MEK pro- tein only in the cases expressing phospho-ERK (6/11; Figure 2B top panel and data not shown). MEC1 cells also showed constitutively phosphorylated MEK, while similar levels of MEK phosphorylation were detected in Daudi only after activa- tion with anti-IgM antibodies (data not shown).
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(16.2 °C) was inferior to 20 or 30 °C at which we previously ob- served the highest antibacterial and PO activities (Catalán et al., 2012). However we expected that thermal preferences should match temperatures optimal for physiological traits, in this case immune response, it is very common that thermal preferences are close to body temperatures that maximize various measures of physiological performance instead one in particular (Martin and Huey, 2008). In this sense, Murdock and collaborators (2012) reported different temperatures at which different immune traits showed their maximal expressions. In the malaria vector Anopheles stephensi, nitric oxide synthase expression peaked at 30 °C, cecr- opin expression was not signiﬁcantly affected by temperature and humoral melanization, and phagocytosis and defensin expres- sion peaked around 18 °C (Murdock et al., 2012). Then, total ﬁtness over time might be maximized – at least in a variable environment – by centering thermal preferences at a temperature below the body temperature that maximizes physiological responses like immunity (Martin and Huey, 2008), because ﬁtness may drop rap- idly at temperatures above the optimum due to the nonlinear and highly asymmetrical shape of ﬁtness curves of ectotherms (Huey and Stevenson, 1979).
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