Specific Immune Mechanisms Research Articles

Immune changes beyond Th2 pathways during rapid multifood immunotherapy enabled with omalizumab.

Multifood oral immunotherapy (mOIT) with adjunctive anti-IgE (omalizumab, XOLAIR® ) treatment affords safe, effective, and rapid desensitization to multiple foods, although the specific immune mechanisms mediating this desensitization remain to be fully elucidated. Participants in our phase 2 mOIT trial (NCT02643862) received omalizumab from baseline to week 16 and mOIT from week 8 to week 36. We compared the immune profile of PBMCs and plasma taken at baseline, week 8, and week 36 using high-dimensional mass cytometry, component-resolved diagnostics, the indirect basophil activation test, and Luminex. We found (i) decreased frequency of IL-4+ peanut-reactive CD4+ T cells and a marked downregulation of GPR15 expression and CXCR3 frequency among γδ and CD8+ T-cell subsets at week 8 during the initial, omalizumab-alone induction phase; (ii) significant upregulation of the skin-homing receptor CCR4 in peanut-reactive CD4+ T and Th2 effector memory (EM) cells and of cutaneous lymphocyte-associated antigen (CLA) in peanut-reactive CD8+ T and CD8+ EM cells; (iii) downregulation of CD86 expression among antigen-presenting cell subsets; and (iv) reduction in pro-inflammatory cytokines, notably IL-17, at week 36 post-OIT. We also observed significant attenuation of the Th2 phenotype post-OIT, defined by downregulation of IL-4 peanut-reactive T cells and OX40 in Th2EM cells, increased allergen component-specific IgG4/IgE ratio, and decreased allergen-driven activation of indirectly sensitized basophils. This exploratory study provides novel comprehensive insight into the immune underpinnings of desensitization through omalizumab-facilitated mOIT. Moreover, this study provides encouraging results to support the complex immune changes that can be induced by OIT.

Neutrophil Cells Are Essential for The Efficacy of a Therapeutic Vaccine against Paracoccidioidomycosis.

Paracoccidioidomycosis (PCM), caused by the Paracoccidioides species, is a systemic disease endemic in several Latin American countries, mainly in Brazil, Colombia, Argentina, and Venezuela. Current treatment approaches are challenging as they require prolonged durations of antifungal drugs that have potential toxicities, and despite antifungals, relapses are common. Hence, new therapeutic approaches, such as vaccines, are being investigated. The therapeutic vaccine consisting of peptide P10 associated with lipid cationic DODAB (P10+DODAB) is effective in murine models of PCM. However, the specific immune mechanisms required for the protective response has not been fully elucidated. The present work aims at evaluating the participation of neutrophils in the immune response induced by P10+DODAB. We found that the vaccine reduced both the influx of pulmonary neutrophils and the fungal load in comparison to infected animals that did not receive this treatment. The parenchymal architecture of the lungs of P10+DODAB-treated animals was largely preserved with only a few granulomas present, and tissue cytokine analysis showed a Th1 cytokine profile with augmented levels of IL-12, IFN-γ and TNF-α, and low levels of IL-4. When neutrophils were depleted 24 h prior to each treatment, the effectiveness of the P10+DODAB vaccine was completely lost as the fungal burdens remained high and histological examination showed a marked inflammation and fungal dissemination with a dysregulated cytokine response. In conclusion, these findings indicate that neutrophils are vital to ensure the triggering of an effective immune response to P10+DODAB.

Intraspecific variation in immune gene expression and heritable symbiont density.

Host genetic variation plays an important role in the structure and function of heritable microbial communities. Recent studies have shown that insects use immune mechanisms to regulate heritable symbionts. Here we test the hypothesis that variation in symbiont density among hosts is linked to intraspecific differences in the immune response to harboring symbionts. We show that pea aphids (Acyrthosiphon pisum) harboring the bacterial endosymbiont Regiella insecticola (but not all other species of symbionts) downregulate expression of key immune genes. We then functionally link immune expression with symbiont density using RNAi. The pea aphid species complex is comprised of multiple reproductively-isolated host plant-adapted populations. These 'biotypes' have distinct patterns of symbiont infections: for example, aphids from the Trifolium biotype are strongly associated with Regiella. Using RNAseq, we compare patterns of gene expression in response to Regiella in aphid genotypes from multiple biotypes, and we show that Trifolium aphids experience no downregulation of immune gene expression while hosting Regiella and harbor symbionts at lower densities. Using F1 hybrids between two biotypes, we find that symbiont density and immune gene expression are both intermediate in hybrids. We propose that in this system, Regiella symbionts are suppressing aphid immune mechanisms to increase their density, but that some hosts have adapted to prevent immune suppression in order to control symbiont numbers. This work therefore suggests that antagonistic coevolution can play a role in host-microbe interactions even when symbionts are transmitted vertically and provide a clear benefit to their hosts. The specific immune mechanisms that we find are downregulated in the presence of Regiella have been previously shown to combat pathogens in aphids, and thus this work also highlights the immune system's complex dual role in interacting with both beneficial and harmful microbes.

Microbiota regulate innate immune signaling and protective immunity against cancer

Microbiota play critical roles in regulating colitis and colorectal cancer (CRC). However, it is unclear how the microbiota generate protective immunity against these disease states. Here, we find that loss of the innate and adaptive immune signaling molecule, TAK1, in myeloid cells (Tak1ΔM/ΔM) yields complete resistance to chemical-induced colitis and CRC through microbiome alterations that drive protective immunity. Tak1ΔM/ΔM mice exhibit altered microbiota that are critical for resistance, with antibiotic-mediated disruption ablating protection and Tak1ΔM/ΔM microbiota transfer conferring protection against colitis or CRC. The altered microbiota of Tak1ΔM/ΔM mice promote IL-1β and IL-6 signaling pathways, which are required for induction of protective intestinal Th17 cells and resistance. Specifically, Odoribacter splanchnicus is abundant in Tak1ΔM/ΔM mice and sufficient to induce intestinal Th17 cell development and confer resistance against colitis and CRC in wild-type mice. These findings identify specific microbiota strains and immune mechanisms that protect against colitis and CRC.

Allergy to penicillin and betalactam antibiotics.

ABSTRACTBetalactams are the most frequent cause of hypersensitivity reactions to drugs mediated by a specific immune mechanism. Immediate reactions occur within 1 to 6 hours after betalactam administration, and are generally IgE-mediated. They clinically translate into urticaria, angioedema and anaphylaxis. Non-immediate or delayed reactions occur after 1 hour of administration. These are the most common reactions and are usually mediated by T cells. The most frequent type is the maculopapular or morbilliform exanthematous eruption. Most individuals who report allergies to penicillin and betalactams can tolerate this group of antibiotics. To make diagnosis, a detailed medical history is essential to verify whether it was an immediate or non-immediate reaction. Thereafter, in vivo and/or in vitro tests for investigation may be performed. The challenging test is considered the gold standard method for diagnosis of betalactam hypersensitivity. The first approach when suspecting a reaction to betalactam is to discontinue exposure to the drug, and the only specific treatment is desensitization, which has very precise indications. The misdiagnosis of penicillin allergy affects the health system, since the “penicillin allergy” label is associated with increased bacterial resistance, higher rate of therapeutic failure, prolonged hospitalizations, readmissions, and increased costs. Thus, it is essential to develop strategies to assist the prescription of antibiotics in patients identified with a label of “betalactam allergy” at hospitals, and to enhance education of patients and their caregivers, as well as of non-specialist physicians.

Comparative assessment of immune evasion mechanisms in human whole-blood infection assays by a systems biology approach.

Computer simulations of mathematical models open up the possibility of assessing hypotheses generated by experiments on pathogen immune evasion in human whole-blood infection assays. We apply an interdisciplinary systems biology approach in which virtual infection models implemented for the dissection of specific immune mechanisms are combined with experimental studies to validate or falsify the respective hypotheses. Focusing on the assessment of mechanisms that enable pathogens to evade the immune response in the early time course of a whole-blood infection, the least-square error (LSE) as a measure for the quantitative agreement between the theoretical and experimental kinetics is combined with the Akaike information criterion (AIC) as a measure for the model quality depending on its complexity. In particular, we compare mathematical models with three different types of pathogen immune evasion as well as all their combinations: (i) spontaneous immune evasion, (ii) evasion mediated by immune cells, and (iii) pre-existence of an immune-evasive pathogen subpopulation. For example, by testing theoretical predictions in subsequent imaging experiments, we demonstrate that the simple hypothesis of having a subpopulation of pre-existing immune-evasive pathogens can be ruled out. Furthermore, in this study we extend our previous whole-blood infection assays for the two fungal pathogens Candida albicans and C. glabrata by the bacterial pathogen Staphylococcus aureus and calibrated the model predictions to the time-resolved experimental data for each pathogen. Our quantitative assessment generally reveals that models with a lower number of parameters are not only scored with better AIC values, but also exhibit lower values for the LSE. Furthermore, we describe in detail model-specific and pathogen-specific patterns in the kinetics of cell populations that may be measured in future experiments to distinguish and pinpoint the underlying immune mechanisms.

POS-209 IMMUNE CHECKPOINTS INHIBITORS-ASSOCIATED ACUTE KIDNEY INJURY: A SINGLE-CENTRE STUDY

Immune checkpoints inhibitors (ICPi) have transformed the treatment and prognosis in patients with various malignancies. Having specific immune mechanism of action, these drugs can cause immune-related adverse events, including acute kidney injury (AKI). Our aim was to investigate the incidence, management, and outcomes of patients with ICPi-associated AKI.

Preliminary analysis of immunoregulatory mechanism of hyperhomocysteinemia-induced brain injury in Wistar-Kyoto rats.

Hyperhomocysteinemia (HHcy) can be used as an independent risk factor for predicting cardiovascular disease, stroke and vitamin B12 deficiency. Patients with HHcy have elevated plasma homocysteine (Hcy) concentrations. Enhancing cerebrovascular permeability of substances such as Hcy and brain damage will synergistically increase the symptoms of hypertension, but the specific immune regulation mechanism is still not clear. The purpose of the present study was to preliminarily explore the immunomodulatory mechanism of brain damage caused by HHcy in Wistar-Kyoto (WKY) rats. A total of 60 WKYs were randomly divided into three groups: WKY control group (WKY-C group), WKY methionine group (WKY-M group) and WKY treatment group (WKY-T group; vitamin B6, B12 and folic acid were used as treatment), with 20 rats in each group. Physical examination of body weight, systolic blood pressure (SBP) and plasma Hcy content was performed routinely. The concentration of cytokines, including IL-6, IL-10, IL-17A and TGF-β, associated with T helper cell 17 (Th17) and regulatory T (Treg) cells and key regulator genes, including retinoic acid-related orphan receptor γ t (RORγt) and forkhead box P3 (FoxP3), were detected by ELISA, reverse transcription-quantitative PCR and western blotting. Th17/Treg lymphocytes were determined by flow cytometry. MRI scan was preliminarily used to detect the changes characteristic of the ischemic stroke. The results revealed that high methionine diets might have a significant effect on the body weight and SBP. The inflammatory response effect of Treg cells was significantly inhibited in the WKY-M group, and that of Th17 cells was upregulated when compared to the WKY-T group. Compared with the WKY-T group, the expression levels of IL-17A and RORγt in the WKY-M group were significantly upregulated, while the mRNA levels of FoxP3 in the WKY-M group were significantly downregulated. The diet intervention (including vitamins B6 and B12 and folic acid) could reduce the level of Hcy in the blood, but also reduce the inflammatory response and rectify the Treg/Th17 immune imbalance to ameliorate the brain tissue damage. In conclusion, the present study indicated that HHcy can promote inflammation by triggering Treg/Th17 immune imbalance to ameliorate the brain tissue damage.

The Role of Immunity in Fighting and Checking the Spread of Viral Diseases

Immunology is truly a fascinating discipline that meets the challenge and offers opportunity in fighting and checking the spread of diseases. Many viruses infect humans. The host response to invading virus depends upon the infectious agents and where it is encountered. In response to virus entry there may not be, always, an overt reaction leading to clinical manifestation. There may be simply, subclinical infection, which would protect the individual from later exposure. A number of specific immune effector mechanisms together with non-specific defence mechanism play role in eliminating an infective virus.

Reactive Oxygen Species Interact With NLRP3 Inflammasomes and Are Involved in the Inflammation of Sepsis: From Mechanism to Treatment of Progression.

Over the past 10 years, the crisis of sepsis has remained a great challenge. According to data from 2016, the sepsis-related mortality rate remains high. In addition, sepsis consumes extensive medical resources in intensive care units, and anti-inflammatory agents fail to improve sepsis-associated hyperinflammation and symptoms of immunosuppression. The specific immune mechanism of sepsis remains to be elucidated. Reactive oxygen species (ROS) are triggered by energy metabolism and respiratory dysfunction in sepsis, which not only cause oxidative damage to tissues and organelles, but also directly and indirectly promote NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. NLRP3 inflammasomes enlarge the inflammatory response and trigger apoptosis of immune cells to exacerbate sepsis progression. Inhibiting the negative effects of ROS and NLRP3 inflammasomes therefore provides the possibility of reversing the excessive inflammation during sepsis. In this review, we describe the interaction of ROS and NLRP3 inflammasomes during sepsis, provide prevention strategies, and identify fields that need further study.

A Methylation-Based Reclassification of Bladder Cancer Based on Immune Cell Genes.

Simple SummaryBladder cancer (BC) development is highly related to immune cell infiltration. In this study, we aimed to construct a new classification of bladder cancer molecular subtypes based on immune-cell-associated CpG(Methylation) sites. The classification was accurate and stable. BC patients were successfully divided into three subtypes based on the immune-cell-associated CpG sites. The clinicopathologic features, distribution of immune cells, level of expression of checkpoints, stromal score, immune score, ESTIMATEScore, tumor purity, APC co_inhibition, APC co_stimulation, HLA, MHC class_I, Type I IFN_respons, Type II IFN response, and DNA stemness score (DNAss) presented significant differences among the three subgroups. The specific genomic alteration was also different across subgroups. High-level immune infiltration showed a correlation with high-level methylation. A lower RNA stemness score (RNAss) was associated with higher immune infiltration. Cluster 2 demonstrated a better response to chemotherapy. The anti-cancer targeted drug therapy results are different among the three subgroups.Background: Bladder cancer is highly related to immune cell infiltration. This study aimed to develop a new classification of BC molecular subtypes based on immune-cell-associated CpG sites. Methods: The genes of 28 types of immune cells were obtained from previous studies. Then, methylation sites corresponding to immune-cell-associated genes were acquired. Differentially methylated sites (DMSs) were identified between normal samples and bladder cancer samples. Unsupervised clustering analysis of differentially methylated sites was performed to divide the sites into several subtypes. Then, the potential mechanism of different subtypes was explored. Results: Bladder cancer patients were divided into three groups. The cluster 3 subtype had the best prognosis. Cluster 1 had the poorest prognosis. The distribution of immune cells, level of expression of checkpoints, stromal score, immune score, ESTIMATEScore, tumor purity, APC co_inhibition, APC co_stimulation, HLA, MHC class_I, Type I IFN Response, Type II IFN Response, and DNAss presented significant differences among the three subgroups. The distribution of genomic alterations was also different. Conclusions: The proposed classification was accurate and stable. BC patients could be divided into three subtypes based on the immune-cell-associated CpG sites. Specific biological signaling pathways, immune mechanisms, and genomic alterations were varied among the three subgroups. High-level immune infiltration was correlated with high-level methylation. The lower RNAss was associated with higher immune infiltration. The study of the intratumoral immune microenvironment may provide a new perspective for BC therapy.

Evolution of views on plant immunity: from Flor’s “gene-for-gene” theory to the “zig-zag model” developed by Jones and Dangl

The study of plant defence mechanisms in response to pathogens in the mid-20th century resulted in Harold Flor’s gene-for-gene interaction hypothesis, which became recognised as central to the study of phytoimmunity. According to this theory, the outcome of interactions in plant – pathogen phytopathosystems – i.e. compatibility or incompatibility – is controlled genetically in interacting organisms and determined by the presence of specific genes in both pathogen and plant: resistance genes in the plant and avirulence genes in pathogen. The latest achievements in phytoimmunology, obtained with the help of modern molecular biology and bioinformatics methods, have made a significant contribution to the classical understanding of plant immunity and provided grounds for a modern concept of phytoimmunity consisting in the “zig-zag model” developed by Jonathan Jones and Jefferey Dangl. Plant immunity is currently understood as being determined by an innate multi-layer immune system involving various structures and mechanisms of specific and non-specific immunity. Recognition by plant membrane receptors of conservative molecular patterns associated with microorganisms, as well as molecules produced during cell wall disruption by pathogen hydrolytic enzymes forms a basic non-specific immune response in the plant. Detection of pathogen effector molecules by plant intra-cellular receptors triggers a specific effector-triggered immunity, resulting in the development of the hypersensitive response, systemic resistance and immune memory of the plant. Virulence factors and pathogen attack strategies on the one hand, and mechanisms of plant immune protection on the other, are the result of one form of constant co-evolution, often termed an “evolutionary arms race”. This paper discusses the main principles of Flor's classical “gene-for-gene interaction” theory as well as the molecular-genetic processes of plant innate immunity, their mechanisms and participants in light of contemporary achievements in phytoimmunology.

Immune pathogenesis of COVID-19-related multisystem inflammatory syndrome in children.

Several important features of Multisystem Inflammatory Syndrome in Children (MIS-C) differentiate it from Kawasaki disease. Rowley et al. discuss what is known about MIS-C and the need to elucidate the specific immune mechanisms underlying hyperinflammatory syndromes caused by SARS-CoV-2 to advance potential targeted treatments and prevention efforts.

GWAS-Based Discoveries in IgA Nephropathy, Membranous Nephropathy, and Steroid-Sensitive Nephrotic Syndrome.

Over the past decade, genome-wide association studies (GWAS) have emerged as a powerful tool to understand the genetic basis of complex traits in humans. The GWAS approach has been successfully applied to primary glomerular disorders, providing numerous novel insights into the genetic architecture of IgA nephropathy, membranous nephropathy, and steroid-sensitive nephrotic syndrome. IgA nephropathy appears to have a highly complex polygenic architecture, with nearly 20 genome-wide significant loci of small-to-moderate effects discovered to date. In contrast, the genetic susceptibility to membranous nephropathy and steroid-sensitive nephrotic syndrome appears to be driven by a small number of large-effect loci. The MHC locus on chromosome 6p21 is strongly associated with genetic susceptibility to all major types of immune-mediated glomerulopathies. However, a distinct set of classical HLA alleles is associated with each individual disease type, pinpointing to specific immune mechanisms underlying each of these conditions. Additional insights from the discovery of non-HLA risk loci reinforced the role of innate and adaptive immunity in the pathogenesis of these disorders, and highlighted important susceptibility overlaps between glomerular and other autoimmune and inflammatory conditions. Despite these initial successes, much larger GWAS and sequencing studies are still needed for each individual glomerular disease type. Increased power will be critical to comprehensively test for genetic effects across the full spectrum of allelic frequencies, to detect gene-gene and gene-environment interactions, and to potentially improve the performance of polygenic risk predictors. Moreover, the existing studies are limited mostly to European and East Asian populations, stressing the urgency to expand genetic discovery efforts to more diverse populations worldwide.

Profiles of Immune Infiltration and Prognostic Immunoscore in Lung Adenocarcinoma.

Lung tissue is abundant with immune cells that form a powerful first defense against exotic particles and microbes. The malignant phenotype of lung adenocarcinoma (LUAD) is defined not only by intrinsic tumor cells but also by tumor-infiltrating immune cells (TIICs) recruited to the immune microenvironment. Understanding more about the immune microenvironment of LUAD could function in sorting out patients more likely with high risk and benefit from immunotherapy. Twenty-two types of TIICs were estimated based on large public LUAD cohorts from the TCGA and GEO datasets using the CIBERSORT algorithm. Then principal component analysis (PCA), meta-analysis, and single-sample gene set enrichment analysis (ssGSEA) were used to measure and evaluate the specific immune responses and relative mechanisms. Moreover, an immunoscore model based on the percent of immune cells was constructed via the univariate and multivariate Cox regression models, which provided an in-depth overview of the LUAD immune microenvironment and shed light on the immune regulatory mechanism. The differential expression genes (DEGs) were acquired based on the immunoscore model, and prognostic immune-related genes were further identified. GSEA and the protein–protein interaction network (PPI) further revealed that these genes were mostly enriched in many immune-related biological processes. It is hoped that this immune landscape could provide a more accurate understanding for LUAD development and tumor immune therapy.

Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity

The transcription factor JUN is highly expressed in pulmonary fibrosis. Its induction in mice drives lung fibrosis, which is abrogated by administration of anti-CD47. Here, we use high-dimensional mass cytometry to profile protein expression and secretome of cells from patients with pulmonary fibrosis. We show that JUN is activated in fibrotic fibroblasts that expressed increased CD47 and PD-L1. Using ATAC-seq and ChIP-seq, we found that activation of JUN rendered promoters and enhancers of CD47 and PD-L1 accessible. We further detect increased IL-6 that amplified JUN-mediated CD47 enhancer activity and protein expression. Using an in vivo mouse model of fibrosis, we found two distinct mechanisms by which blocking IL-6, CD47 and PD-L1 reversed fibrosis, by increasing phagocytosis of profibrotic fibroblasts and by eliminating suppressive effects on adaptive immunity. Our results identify specific immune mechanisms that promote fibrosis and suggest a therapeutic approach that could be used alongside conventional anti-fibrotics for pulmonary fibrosis.

HLA studies in the context of coronavirus outbreaks.

Little is known at the moment about specific immune mechanisms that would work against SARS-CoV-2, although such knowledge is expected to play a vital role. In this context, a particular focus has to be given to the human leucocyte antigen system that governs our adaptive immunity.

Marine actinomycetes Nocardiopsis alba MCCB 110 has immunomodulatory property in the tiger shrimp Penaeus monodon

Shrimp farming constitutes an important source of revenue and employment in many developing countries. However, the shrimp industry has always been plagued with infectious diseases having varied aetiologies. Dominated by non - specific immune mechanism, preventive health care strategy is the most appropriate approach to protect the crop. The present study evaluated the efficacy of an actinomycete, Nocardiopsis alba MCCB 110 in eliciting non - specific immune mechanism in Penaeus monodon having Vibrio harveyi as the challenge organism. Haemocyte count, total protein, phenoloxidase, reactive oxygen intermediates, acid and alkaline phosphatase as well as the gene expression of proPO, peroxinectin, transglutaminase, alpha 2-macroglobulin, astakine, crustin, and penaeidin-3 were evaluated. The results demonstrated that the phenoloxidase, respiratory burst, total protein, acid and alkaline phosphatases were higher in the haemolymph of shrimps fed with Nocardiopsis alba MCCB 110 incorporated feed before and after challenge with Vibrio harveyi, compared to those of placebo fed animals. Up-regulation of six immune genes (alpha 2 macroglobulin, penaeidin −3, transglutaminase, proPO, crustin and peroxinectin) during the post-challenge were recorded. Survival of shrimp among the Nocardiopsis alba administered ones was 83% while it was 50% in placebo fed group. The elevated levels of nonspecific immune gene transcripts and concurrent increase in non specific immunity besides the higher survival rate in the Nocardiopsis alba administered group demonstrated the immunomodulatory property of the marine actinomycete Nocardiopsis alba MCCB 110 in the tiger shrimp Penaeus monodon, and on administering it through diet shrimp could be protected from vibriosis especially of V. harveyi.

Mifepristone (RU486) Inducing Abortion in a Mouse Model by Regulating Innate and Adaptive Immune Responses

Objective: Mifepristone (RU486), one of the most common medications for artificial abortion, attenuates the immunoregulatory effects of progesterone. However, the specific immune regulatory mechanism of RU486 in abortion remains unknown. We intended to investigate the immunomodulatory effects of RU486 on abortion. Methods: Sixty female mice were divided into the control group (0 mg RU486) and RU486 group (2 mg/kg RU486). The uterus, peripheral blood, and spleen were obtained for isolation of specific cell types. The population and phenotype of immune cells in the decidua, peripheral blood, and spleen were analyzed using flow cytometry. Statistical differences between groups were determined using two-tailed t- test. For all statistical tests, P < 0.05 was considered statistically significant. Results: RU486 effectively induced abortion in pregnant mice, with a significantly higher number of decidual macrophages (dMφ) (control group = 25.55% ± 2.467%, RU486 group = 19.41% ± 1.423%; P < 0.05), especially the major histocompatibility complex IIhigh subset. No difference in Mφ number was observed in the spleen or peripheral blood. Moreover, the dMφ from mice with RU486-induced abortion displayed a remarkable activated phenotype, with increased expressions of inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin (IL)-12 but decreased expressions of arginase-1 and IL-10. We also found elevated levels of decidual CD4+ T-cells in the RU486 group that exhibited a higher level of the proinflammatory cytokine interferon-γ and a lower level of the anti-inflammatory cytokines, IL-4 and IL-10. Conclusions: We report a new mechanism of RU486-induced abortion via the regulation of innate cell Mφ activation and the adaptive response of CD4+ T-cells present in the decidua but not the periphery.

The CD200-CD200R cross-talk helps Leishmania donovani to down regulate macrophage and CD4+CD44+ T cells effector functions in an NFκB independent manner

The lacuna in the knowledge of immunobiology, especially in visceral infections that are fatal if left untreated, are a major hurdle in getting a vaccine candidate for leishmaniasis. Till date, only a few drugs are available to combat human leishmaniasis and a vaccine candidate either prophylactic or preventive is still awaited. Therefore, identification of host and parasitic factors involved in the regulation of specific immune mechanisms are essentially needed. In this study, we observed that CD200-CD200R immune inhibitory axis regulates host macrophages effectors properties and helps antigen experienced T cells (CD4+CD44+ T cells) to acquire anti-inflammatory cytokines (IL-4, IL-10, TGF-β, IL-27) producing abilities in an NFkB independent manner. After CD200 blocking the macrophages effectively inhibited proliferation of Leishmania amastigotes and also induced the production of IL-12, IFN-γ, TNF-α and nitric oxide (NOx). Further, the blocking of CD200 signaling also restored macrophages MHC-II expression and helped CD4+CD44+ T cells to produce pro-inflammatory cytokines like IL-2, IL-12 and IFN-γ. The finding of this study suggested the importance of immune inhibitory mechanisms in controlling Leishmania growth and survival and therefore, requires more studies to understand its role in vaccine induced immunity.