Multiple Immune Mechanisms Research Articles

Pediatric Immune Thrombocytopenia: The Impact of Antithyroid Antibodies on the Treatment Outcomes

Immune thrombocytopenic purpura (ITP) is an acquired immune-mediated bleeding disorder characterized by isolated low platelet (PLT) counts. Immune thrombocytopenic purpura pathogenesis involves multiple immune mechanisms causing PLT destruction and inadequate production. Owing to impaired immune homeostasis, ITP patients can develop other than anti-PLT autoantibodies even in the absence of clinical signs of autoimmune disease, such as anti-thyroglobulin (TG) and anti-thyroperoxidase (TPO) antibodies. Our objective is to determine the prevalence of antithyroid antibodies (ATAs) in the population of pediatric ITP patients, and the differences in ATA positivity prevalence in newly diagnosed/persistent ITP, and chronic ITP patient subgroups, as well as to establish the impact of ATA positivity on the treatment outcomes. A cross-sectional observational study was conducted involving 75 pediatric patients diagnosed with ITP and 60 healthy controls, carried out over a period of 11 years. The prevalence of ATA was significantly higher in ITP patients compared with controls (28% vs 5%, P < .05). Initial PLT count was significantly lower in ATA-positive patients, but the treatment response did not differ between ATA-positive and ATA-negative patients. To conclude, our study confirmed that ITP patients have a higher prevalence of ATA compared with the healthy pediatric population; however, no association was found between ATA positivity and disease duration or treatment outcomes. Our findings suggest that ATA screening may not be prognostic for ITP in pediatric population, but further research with larger cohorts may be beneficial to elucidate the role of ATA in ITP pathogenesis and management.

PvDBPII elicits multiple antibody-mediated mechanisms that reduce growth in a Plasmodium vivax challenge trial

The receptor-binding domain, region II, of the Plasmodium vivax Duffy binding protein (PvDBPII) binds the Duffy antigen on the reticulocyte surface to mediate invasion. A heterologous vaccine challenge trial recently showed that a delayed dosing regimen with recombinant PvDBPII SalI variant formulated with adjuvant Matrix-MTM reduced the in vivo parasite multiplication rate (PMR) in immunized volunteers challenged with the Thai P. vivax isolate PvW1. Here, we describe extensive analysis of the polyfunctional antibody responses elicited by PvDBPII immunization and identify immune correlates for PMR reduction. A classification algorithm identified antibody features that significantly contribute to PMR reduction. These included antibody titre, receptor-binding inhibitory titre, dissociation constant of the PvDBPII-antibody interaction, complement C1q and Fc gamma receptor binding and specific IgG subclasses. These data suggest that multiple immune mechanisms elicited by PvDBPII immunization are likely to be associated with protection and the immune correlates identified could guide the development of an effective vaccine for P. vivax malaria. Importantly, all the polyfunctional antibody features that correlated with protection cross-reacted with both PvDBPII SalI and PvW1 variants, suggesting that immunization with PvDBPII should protect against diverse P. vivax isolates.

Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

Differential expression profile of genes involved in the immune response associated to progression of chronic Chagas disease.

Patients with chronic Chagas disease present marked clinical and immunological heterogeneity. During the disease, multiple immune mechanisms are activated to fight the parasite. The purpose of this study was to investigate the expression patterns of genes involved in relevant immunological processes throughout the disease in patients with chronic Chagas disease. High-throughput RT-qPCR with QuantStudio 12K Flex real-time PCR system was used to evaluate the expression of 106 immune-related genes in PBMC from a cohort of cardiac Chagas disease patients (CCC I), asymptomatic patients (IND) and healthy donors (HD) after being stimulated with T. cruzi soluble antigens. Principal component analysis (PCA), cluster analysis and volcano plots were used to identify differentially expressed genes. In addition, gene set enrichment analysis (GSEA) was employed to identify the enriched immunological pathways in which these genes are involved. PCA revealed the existence of a statistically divergent expression profile of the 36 genes correlated with PC1 between CCC I patients and HD (p < 0.0001). Differential gene expression analysis revealed upregulation of 41 genes (expression fold-change > 1.5) and downregulation of 14 genes (expression fold-change < 0.66) (p = 8.4x10-13 to p = 0.007) in CCC I patients versus HD. Furthermore, significant differences in the expression level of specific genes have been identified between CCC I and IND patients (8 up and 1 downregulated). GSEA showed that several upregulated genes in CCC I patients participate in immunological pathways such as antigen-dependent B cell activation, stress induction of HSP regulation, NO2-dependent IL12 pathway in NK cells, cytokines-inflammatory response and IL-10 anti-inflammatory signaling. Cardiac Chagas disease patients show an antigen-specific differential gene expression profile in which several relevant immunological pathways seem to be activated. Assessment of gene expression profiles reveal unique insights into the immune response that occurs along chronic Chagas disease.

Synthetic multiantigen MVA vaccine COH04S1 and variant-specific derivatives protect Syrian hamsters from SARS-CoV-2 Omicron subvariants

Emerging SARS-CoV-2 Omicron subvariants continue to disrupt COVID-19 vaccine efficacy through multiple immune mechanisms including neutralizing antibody evasion. We developed COH04S1, a synthetic modified vaccinia Ankara vector that co-expresses Wuhan-Hu-1-based spike and nucleocapsid antigens. COH04S1 demonstrated efficacy against ancestral virus and Beta and Delta variants in animal models and was safe and immunogenic in a Phase 1 clinical trial. Here, we report efficacy of COH04S1 and analogous Omicron BA.1- and Beta-specific vaccines to protect Syrian hamsters from Omicron subvariants. Despite eliciting strain-specific antibody responses, all three vaccines protect hamsters from weight loss, lower respiratory tract infection, and lung pathology following challenge with Omicron BA.1 or BA.2.12.1. While the BA.1-specifc vaccine affords consistently improved efficacy compared to COH04S1 to protect against homologous challenge with BA.1, all three vaccines confer similar protection against heterologous challenge with BA.2.12.1. These results demonstrate efficacy of COH04S1 and variant-specific derivatives to confer cross-protective immunity against SARS-CoV-2 Omicron subvariants.

Highlighting novel targets in immunotherapy for liver cancer

Introduction : Alterations to the hepatic immune microenvironment can play a key role in the development and progression of cancer. This is especially true in the liver due to its evolutionarily conserved immunotolerant state. The presence of chronic inflammation can facilitate the development and progression of hepatocellular carcinoma (HCC) by disrupting the hepatic immune microenvironment. Recently, the addition of the immunotherapy atezolizumab (PD-L1 inhibitor) with bevacizumab (VEGF inhibitor) became the recommended first line systemic treatment for advanced HCC. Areas covered Given recent updates to the guidelines and emerging data on immunotherapy, we herein provide an overview of currently available and novel immunotherapy approaches for the treatment of HCC, including immune checkpoint inhibitors, adoptive cell therapy, and vaccine development. This review performed an extensive literature search to investigate benchwork, clinical research, and clinical trials that evaluate current immunotherapy and establish new targets. Literature was focused on the most up to date research and included ongoing clinical trials to better evaluate the obstacles and future direction of the field. Expert opinion : Given the heterogeneity of HCC tumors, improvement in outcomes will likely come from targeting multiple immune mechanisms. Continued research and clinical trials of combination immunotherapies are necessary to move the field forward.

Bibliometric analysis of tumor necrosis factor in post-stroke neuroinflammation from 2003 to 2021.

Tumor necrosis factor (TNF), a crucial cytokine, has important research value in post-stroke neuroinflammation (PSN). We analyzed the studies that have been conducted in this area and used bibliometric methods to predict research hotspots and identify trends regarding TNF in PSN. Publications were accessed at the Science Citation Index Expanded 1975-2021 (SCI expanded), Web of Science Core Collection (WoSCC), on May 1, 2022. Additionally, software such as CiteSpace and VOSviewer were utilized for bibliometric analyses. In total, 1391 original articles and reviews on TNF in PSN published from 2003 to 2021 were identified. An upward trend was observed in the number of publications on TNF in PSN. These publications were primarily from 57 countries and 1446 institutions, led by China and the United States with China leading the number of publications (NP) and the US with the number of citations (NC). The League of European Research Universities (LERU) and Journal of Neuroinflammation, respectively were the most prolific branches and journals. Zhang, John H. published the most papers and Finsen, Bente had the most cited papers. One paper by Kettenmann, H. published in 2011 reached the highest level of Global Citation Score (GCS). The keyword co-occurrence and reference co-citation analyses suggest that poststroke therapy and potential mechanistic pathways are important topics related to PSN in recent years. Reference burst detection suggests new burst hotspots after 2015, focusing on pathway modulation and discovery of therapeutic targets, suggesting a substantial development in the study of TNF in PSN research. The present bibliometric analysis shows a continuous trend of increasing literature related to TNF in PSN, and shows that TNF plays an important role in PSN involves multiple immune mechanisms and may contribute as a potential target for neuroprotective therapeutics after stroke. Prior to 2011, most of the research was focused on discovering the specific role of TNF in PSN, and in recent years studies have mainly targeted the exploration of the signaling pathways. Future research prospects may lie in finding key therapeutic targets in pathway of TNF in PSN.

Oral vaccine formulation combining tick Subolesin with heat inactivated mycobacteria provides control of cross-species cattle tick infestations

Tick vaccines are necessary as part of a One Health approach for the control of tick infestations and tick-borne diseases. Subolesin (SUB, also known as 4D8) is a tick protective antigen that has shown efficacy in vaccine formulations for the control of ectoparasite infestations and pathogen infection/transmission. A recent proof-of-concept study reported oral vaccination combining Rhipicephalus microplus SUB with heat inactivated Mycobacterium bovis (IV) as an immunostimulant for the control of cattle tick infestations. Based on the efficacy of Rhipicephalus decoloratus SUB for the control of multiple cattle tick species in Uganda, herein we design a controlled pen trial using an oral formulation combining R. decoloratus SUB with IV for the control of R. decoloratus and Rhipicephalus appendiculatus cattle tick infestations. Vaccine efficacy (E) of SUB + IV on tick life cycle was compared with IV and SUB alone and with PBS as control. The IgG antibody titers against SUB and M. bovis P22 and the serum levels of selected protein immune biomarkers (IL-1beta, TNF-alpha, C3) were determined and analyzed as possible correlates of protection. Oral immunization with IV and SUB alone and in SUB + IV combination were effective for the control of tick infestations (E = 71–96% for R. decoloratus and 87–99% for R. appendiculatus) with highest E (higher than 95%) for SUB + IV. The results demonstrated that oral immunization with the SUB + IV formulation resulted in effective control of cattle tick infestations through the activation of multiple immune mechanisms. These results support the application of oral vaccine formulations with SUB + IV for the control of cattle infestations with Rhipicephalus species towards improving animal health.

Abstract LB179: Patient-derived, vaccine-elicited, anti-MUC1 antibodies directly target tumor cells for elimination via multiple immune mechanisms

Abstract During premalignant and malignant transformation, cells undergo antigenic changes that can be recognized by the immune system, and this can be leveraged both for immune prevention and therapy. One such change occurs with MUC1, or Mucin-1, a large variable number tandem repeat (VNTR)-containing transmembrane protein that is overexpressed and hypoglycosylated on a majority of precancerous and adenocarcinoma cells, including those of the colon, lung, breast, pancreas and ovaries. This tumor form of MUC1 is recognized by both cellular and humoral immunity. Healthy individuals at high risk of developing colon cancer due to a history of colonic polyps were enrolled in a clinical trial testing the feasibility of prophylactic vaccination against the tumor form of MUC1, also expressed on polyps (Kimura et al., 2013). Half the participants generated high levels of anti-MUC1 IgG antibodies, some of which were cloned to further analyze their tumor specificity and to potentially develop them as therapeutics for patients with cancer (Lohmueller et al., 2016). As these fully human IgG1 monoclonal antibodies (mAbs) were selected and affinity matured in healthy individuals who experienced no negative side effects to the vaccine in &amp;gt;10 years, it increases the likelihood that as therapeutics they will be safe. To study anti-tumor efficacy and mechanism(s) of action of 12 of these mAbs, tumor cells were co-incubated with immune cells in the presence of the mAbs, and each mAb’s ability to mediate antibody-dependent cellular cytotoxicity (ADCC) by NK cells, antibody-dependent cellular phagocytosis (ADCP) by monocytes, antibody-dependent trogocytosis/trogoptosis (ADCT) by neutrophils, antibody-dependent cytokine release (ADCR) and complement dependent cytotoxicity (CDC) was assessed. Several MUC1 mAbs examined could mediate ADCC, ADCP, ADCT and ADCR, with some mechanisms being cell-line dependent. One mAb was selected for in vivo testing and found to delay breast cancer growth and prolong survival in immunocompromised mice lacking T cells, B cells and NK cells, pointing to ADCP and ADCT as important anti-tumor functions. Additionally, the relationship between epitope location and immune effector functions was explored by creating different MUC1 constructs that vary epitope distance from the cell surface, number of epitopes, etc, to test properties of the target antigen that may affect antibody efficacy. These latter experiments revealed an increased efficiency in phagocytosis and trogocytosis when the mAbs bound an epitope that was both proximal to and anchored to the membrane. Notably, unlike published studies of rituximab and alemtuzumab, the amount of MUC1 mAb binding did not always correlate with increased effector function. Our results may inform not only the development of these MUC1-based therapies but more broadly future therapeutic mAb design against a variety of targets. Citation Format: Michelle L. McKeague, Jason Lohmueller, Matthew T. Dracz, Najla Saadallah, Jia Xue, Eric D. Ricci, William Lu, Olivera J. Finn. Patient-derived, vaccine-elicited, anti-MUC1 antibodies directly target tumor cells for elimination via multiple immune mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB179.

Role of surfactant protein-D in ocular bacterial infection.

PurposeOur review explains the role of surfactant protein D (SP-D) in different kinds of bacterial infection based on its presence in different ocular surface tissues. We discuss the potential role of SP-D against invasion by pathogens, with the aim of identifying new prospects for the possible mechanism of SP-D-mediated immune processes, and the diagnosis, prognosis, or treatment of ocular bacterial infection.MethodsWe reviewed articles about the role of SP-D in various ocular bacterial infections or infection-related ocular diseases through PubMed, Google Scholar, and the Web of Science databases.ResultsSP-D acts as an important immune factor that can resemble molecules in different polymerization states and that defends against pathogen invasion. The increased SP-D production and secretion in tear fluid and the cornea after ocular bacterial infections such as Staphylococcus aureus, Pseudomonas aeruginosa keratitis, and infection-related ocular diseases, was shown to have potential anti-inflammatory effects. The mechanisms of SP-D’s action against ocular bacterial infections include presenting, aggregating, opsonizing, and phagocytizing antigens, as well as regulating anti-bacterial immunity processes, including toll-like receptor-5 (TLR-5) pathway and IL-8 effect, TLR-4 and TLR-2 pathways and other possible ways remained to be elucidated in more detail. The findings demonstrate the potential of SP-D as an important clinical diagnostic biomarker prognosis predictor, and target for ocular immunotherapy.ConclusionSP-D participates in invasion by different ocular bacteria and infection-related ocular diseases through multiple immune mechanisms. This finding provides new prospects for the diagnosis, prognosis and treatment of ocular bacterial infection.

Cancer immunotherapy with oncolytic enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways

Abstract Tumors are adept at escaping the immune response through multiple mechanisms that disrupt key processes. This is observed with immune checkpoint blockade therapies and oncolytic viral therapies that are only effective in limited numbers of cancer patients. Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here we describe the use of virus-like vesicles (VLV) for the delivery of trivalent combination cancer therapy. This high-capacity oncolytic RNA replicon vector was adapted to simultaneously and synergistically stimulate immune cell activation, inhibit an immune checkpoint pathway, and disrupt a pro-tumor pathway by co-delivering interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA), respectively. This trivalent viral vector (designated CARG-2020) was injected intralesionally to subcutaneous MC38 and BNL-T3 tumors, and it eradicated large established tumors in mice. The concurrent modulation of IL-12, IL-17, and PD-L1 pathways by CARG-2020 suppressed tumor recurrence and prolonged overall survival. Treatment of primary tumors by CARG-2020 also resulted in marked inhibition of distal tumors, demonstrating a strong abscopal effect of the agent. Mechanistically, CARG-2020 potently activates Th1-armed immunity in primary tumors and the spleen, and inhibits the expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence in mice and extending their survival makes it a promising candidate for use in human cancer immunotherapy. This work is supported by a National Institute of Health/National Cancer Institute grant (NIH/NCI R01CA262430).

Development of a recombinant vaccine against human onchocerciasis

ABSTRACT Introduction Human onchocerciasis caused by the filarial nematode parasite Onchocerca volvulus remains a major cause of debilitating disease infecting millions primarily in Sub-Saharan Africa. The development of a prophylactic vaccine, along with mass drug administration, would facilitate meeting the goal of onchocerciasis elimination by 2030. Areas covered Models used to study immunity to Onchocerca include natural infection of cattle with Onchocerca ochengi and O. volvulus infective third-stage larvae implanted within diffusion chambers in mice. A vaccine, comprised of two adjuvanted recombinant antigens, induced protective immunity in genetically diverse mice suggesting that it will function similarly in diverse human populations. These antigens were recognized by immune humans and also induced protective immunity against Brugia malayi. We describe the development of a fusion protein composed of the two vaccine antigens with the plan to test the vaccine in cows and non-human primates as a prelude to the initiation of phase 1 clinical trials. Expert opinion The adjuvanted O. volvulus vaccine composed of two antigens Ov-103 and Ov-RAL-2 was shown to be consistently effective at inducing protective immunity using multiple immune mechanisms. The vaccine is ready for further evaluation in other animal models before moving to clinical trials in humans.

Differential Expression of Immune Response Genes in Asymptomatic Chronic Chagas Disease Patients Versus Healthy Subjects.

Infection by the Trypanosoma cruzi parasite causes Chagas disease and triggers multiple immune mechanisms in the host to combat the pathogen. Chagas disease has a variable clinical presentation and progression, producing in the chronic phase a fragile balance between the host immune response and parasite replication that keeps patients in a clinically silent asymptomatic stage for years. Since the parasite is intracellular and replicates within cells, the cell-mediated response of the host adaptive immunity plays a critical role. This function is mainly orchestrated by T lymphocytes, which recognize parasite antigens and promote specific functions to control the infection. However, little is known about the immunological markers associated with this asymptomatic stage of the disease. In this large-scale analysis, the differential expression of 106 immune system-related genes has been analyzed using high-throughput qPCR in T. cruzi antigen-stimulated PBMC from chronic Chagas disease patients with indeterminate form (IND) and healthy donors (HD) from endemic and non-endemic areas of Chagas disease. This analysis revealed that there were no differences in the expression level of most genes under study between healthy donors from endemic and non-endemic areas determined by PCA and differential gene expression analysis. Instead, PCA revealed the existence of different expression profiles between IND patients and HD (p < 0.0001), dependent on the 32 genes included in PC1. Differential gene expression analysis also revealed 23 upregulated genes (expression fold change > 2) and 11 downregulated genes (expression fold change < 0.5) in IND patients versus HD. Enrichment analysis showed that several upregulated genes in IND patients participate in relevant immunological pathways such as antigen-dependent B cell activation, stress induction of HSP regulation, NO2-dependent IL12 pathway in NK cells, and cytokine-inflammatory response. The antigen-specific differential gene expression profile detected in these patients and the relevant immunological pathways that seem to be activated could represent potential biomarkers of the asymptomatic form of Chagas disease, helpful to diagnosis and infection control.

Autoantibody Responses to Apolipoprotein A-I Are Not Diet- or Sex-Linked in C57BL/6 Mice.

Atherosclerosis is responsible for a large percentage of all-cause mortality worldwide, but it is only now beginning to be understood as a complex disease process involving metabolic insult, chronic inflammation, and multiple immune mechanisms. Abs targeting apolipoprotein A-I (ApoA-I) have been found in patients with cardiovascular disease, autoimmune conditions, as well as those with no documented history of either. However, relatively little is known about how these Abs are generated and their relationship to diet and sex. In the current study, we modeled this aspect of autoimmunity using anti–ApoA-I immunization of male and female C57BL/6 mice. Unexpectedly, we found that autoantibodies directed against a single, previously unknown, epitope within the ApoA-I protein developed irrespective of immunization status or dyslipidemia in mice. When total IgG subclasses were analyzed over the course of time, we observed that rather than driving an increase in inflammatory IgG subclasses, consumption of Western diet suppressed age-dependent increases in IgG2b and IgG2c in male mice only. The lack of change observed in female mice suggested that diet and sex might play a combined role in Th1/Th2 balance and, ultimately, in immunity to pathogen challenge. This report demonstrates the need for inclusion of both sexes in studies pertaining to diet and aging and suggests that further study of immunogenic epitopes present in ApoA-I is warranted.

Lifestyle and the presence of helminths is associated with gut microbiome composition in Cameroonians

BackgroundAfrican populations provide a unique opportunity to interrogate host-microbe co-evolution and its impact on adaptive phenotypes due to their genomic, phenotypic, and cultural diversity. We integrate gut microbiome 16S rRNA amplicon and shotgun metagenomic sequence data with quantification of pathogen burden and measures of immune parameters for 575 ethnically diverse Africans from Cameroon. Subjects followed pastoralist, agropastoralist, and hunter-gatherer lifestyles and were compared to an urban US population from Philadelphia.ResultsWe observe significant differences in gut microbiome composition across populations that correlate with subsistence strategy and country. After these, the variable most strongly associated with gut microbiome structure in Cameroonians is the presence of gut parasites. Hunter-gatherers have high frequencies of parasites relative to agropastoralists and pastoralists. Ascaris lumbricoides, Necator americanus, Trichuris trichiura, and Strongyloides stercoralis soil-transmitted helminths (“ANTS” parasites) significantly co-occur, and increased frequency of gut parasites correlates with increased gut microbial diversity. Gut microbiome composition predicts ANTS positivity with 80% accuracy. Colonization with ANTS, in turn, is associated with elevated levels of TH1, TH2, and proinflammatory cytokines, indicating an association with multiple immune mechanisms. The unprecedented size of this dataset allowed interrogation of additional questions—for example, we find that Fulani pastoralists, who consume high levels of milk, possess an enrichment of gut bacteria that catabolize galactose, an end product of lactose metabolism, and of bacteria that metabolize lipids.ConclusionsThese data document associations of bacterial microbiota and eukaryotic parasites with each other and with host immune responses; each of these is further correlated with subsistence practices.

Microenvironment of ruptured cerebral aneurysms discovered using data driven analysis of gene expression.

BackgroundIt is well known that ruptured intracranial aneurysms are associated with substantial morbidity and mortality, yet our understanding of the genetic mechanisms of rupture remains poor. We hypothesize that applying novel techniques to the genetic analysis of aneurysmal tissue will yield key rupture-associated mechanisms and novel drug candidates for the prevention of rupture.MethodsWe applied weighted gene co-expression networks (WGCNA) and population-specific gene expression analysis (PSEA) to transcriptomic data from 33 ruptured and unruptured aneurysm domes. Mechanisms were annotated using Gene Ontology, and gene network/population-specific expression levels correlated with rupture state. We then used computational drug repurposing to identify plausible drug candidates for the prevention of aneurysm rupture.ResultsNetwork analysis of bulk tissue identified multiple immune mechanisms to be associated with aneurysm rupture. Targeting these processes with computational drug repurposing revealed multiple candidates for preventing rupture including Btk inhibitors and modulators of hypoxia inducible factor. In the macrophage-specific analysis, we identify rupture-associated mechanisms MHCII antigen processing, cholesterol efflux, and keratan sulfate catabolism. These processes map well onto several of highly ranked drug candidates, providing further validation.ConclusionsOur results are the first to demonstrate population-specific expression levels and intracranial aneurysm rupture, and propose novel drug candidates based on network-based transcriptomics.

Compartmentalized gut lymph node drainage dictates adaptive immune responses.

The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure in such balance leads to severe diseases such as inflammatory bowel diseases (IBD), food allergies or invasive gastrointestinal infections1. Multiple immune mechanisms are therefore in place to maintain tissue integrity, including balanced generation of effector T (TH) cells and FOXP3+ regulatory T (pTreg) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively1–4. The gut–draining lymph nodes (gLNs) are critical sites for orchestrating adaptive immunity to luminal perturbations5–7. However, how they manage to simultaneously support tolerogenic and inflammatory reactions is incompletely understood. Here we report that gLNs are immunologically unique according to the functional gut segment they drain. Stromal and dendritic cell gene signatures as well as T cell polarization against the same luminal antigen differed between gLNs, the proximal small intestine–draining gLNs preferentially giving rise to tolerogenic and the distal gLNs to pro-inflammatory T cell responses. This segregation permitted targeting distal gLNs for vaccination and maintenance of duodenal pTreg cell induction during colonic infection. Conversely, the compartmentalized dichotomy was perturbed by surgical removal of select distal gLNs and duodenal infection, impacting both lymphoid organ and tissue immune responses. Our findings reveal that the conflict between tolerogenic and inflammatory intestinal responses is in part resolved by discrete gLN drainage, and encourage gut segment-specific antigen targeting for therapeutic immune modulation.

Research progress in combination of immunologic adjuvants

Adjuvants enhance the efficacy of the vaccine by regulating or enhancing the immune response to antigens, helping to reduce the amount of antigen and improve the vaccine safety. With the deepening of adjuvant researches, it has been found that the combination of two or more adjuvants can produce synergistic effects by activating multiple immune mechanisms. Highly effective vaccines are urgently needed for the group with pathogens that are difficult to remove and with low immune system function. This requirement can be met by the combination of immunologic adjuvants. In this paper, the progress of some new adjuvants and the applications of combined adjuvants were reviewed including liposomes, immunostimulating complexes, Montanides, polycationic peptide IC31, nanoemulsion and AS adjuvant systems. Key words: Adjuvants; Combined adjuvants; Vaccine

Quis Custodiet Ipsos Custodes? Regulation of Cell-Mediated Immune Responses Following Viral Lung Infections.

Viral lung infections are leading causes of morbidity and mortality. Effective immune responses to these infections require precise immune regulation to preserve lung function after viral clearance. One component of airway pathophysiology and lung injury associated with acute respiratory virus infection is effector T cells, yet these are the primary cells required for viral clearance. Accordingly, multiple immune mechanisms exist to regulate effector T cells, limiting immunopathology while permitting clearance of infection. Much has been learned in recent years about regulation of T cell function during chronic infection and cancer, and it is now clear that many of these mechanisms also control inflammation in acute lung infection. In this review, we focus on regulatory T cells, inhibitory receptors, and other cells and molecules that regulate cell-mediated immunity in the context of acute respiratory virus infection.

Microglial immune checkpoint mechanisms.

Microglia differentiate from progenitors that infiltrate the nascent CNS during early embryonic development. They then remain in this unique immune-privileged environment throughout life. Multiple immune mechanisms, which we collectively refer to as microglial checkpoints, ensure efficient and tightly regulated microglial responses to perturbations in the CNS milieu. Such mechanisms are essential for proper CNS development and optimal physiological function. However, in chronic disease or aging, when a robust immune response is required, such checkpoint mechanisms may limit the ability of microglia to protect the CNS. Here we survey microglial checkpoint mechanisms and their roles in controlling microglial function throughout life and in disease, and discuss how they may be targeted therapeutically.