Diverse Immune Cell Types Research Articles

Inflammatory Basis of Atherosclerosis: Modulation by Sex Hormones.

Atherosclerosis-related cardiovascular diseases (CVDs) are the leading cause of death globally. Several lines of evidence are supportive of the contributory role of vascular inflammation in atherosclerosis. Diverse immune cell types, including monocytes/macrophages, T-cells and neutrophils, as well as specialized proresolving lipid mediators, have been successfully characterized as key players in vascular inflammation. The increased prevalence of atherosclerotic CVD in men in comparison to age-matched premenopausal women and the abolition of sex differences in prevalence during menopause strongly suggest a pivotal role of sex hormones in the development of CVD. Indeed, many animal and human studies conclusively implicate sex hormones as a crucial component in driving the immune response. This is further corroborated by the effective identification of sex hormone receptors in vascular endothelial cells, vascular smooth muscle cells and immune cells. Collectively, these findings suggest a cellular communication between sex hormones and vascular or immune cells underlying the vascular inflammation in atherosclerosis. The aim of this review is to provide an overview of vascular inflammation as a causal cue underlying atherosclerotic CVDs within the context of the modulatory effects of sex hormones. Moreover, the cellular and molecular signaling pathways underlying the sex hormones- immune system interactions as potential culprits for vascular inflammation are highlighted with detailed and critical discussion. Finally, the review concludes by speculations on the potential sex-related efficacy of currently available immunotherapies in mitigating vascular inflammation. Conceivably, a deeper understanding of the immunoregulatory influence of sex hormones on vascular inflammation-mediated atherosclerosis permits sex-based management of atherosclerosis-related CVDs.

The T Cell Receptor Immune Repertoire Protects the Liver From Reconsitution.

Aberrant immune cell infiltrates and microcircumstances represent characteristic features of liver fibrosis. In this study, we profiled the transcriptomes of intrahepatic CD45+ immune cells, from mice, using single-cell RNA sequencing (scRNA-seq) technology to understand the landscape of intrahepatic immune cells during the pathogenesis of fibrosis. Analysis of approximately 10,000 single-cell transcriptomes revealed an increase in dendritic cells (DCs), macrophages, and neutrophils and a decrease in T and natural killer T (NKT) cells. In addition, we report changes in the transcriptomes of diverse immune cell types, implying a deteriorating intrahepatic immune microcircumstance. Furthermore, we uncovered a novel fibrosis-associated CD8 T (Ccl5+, Ccl4+) and CD4 T (mt-Co1+) cell subpopulation, which infiltrates fibrotic liver and is characterized by abnormal activation or inactivation as well as a TCR decline. The results from scRNA-seq and bulk immune repertoire sequencing (IR-seq) revealed an obvious decline in T cell receptor (TCR) clonotypes combined with shrinking VJ and VDJ segment usage, as well as lower complementarity-determining region 3 (CDR3) amino acid (AA) diversity from fibrotic liver. Interestingly, a deficiency of TCR IR (TcrbKO mice) led to a deterioration of liver fibrosis, coupled with activation of hepatic stellate cells (HSCs) induced by the upregulation of macrophage and γδ T cell distribution in fibrotic TcrbKO livers. Our findings reveal the landscape and dynamics of single immune cells in liver fibrosis, and clarify the protective role of TCR IR in response to chronic liver injury.

AHNAK2 is a novel prognostic marker and correlates with immune infiltration in papillary thyroid cancer: Evidence from integrated analysis

Papillary thyroid cancer (PTC) is the most prevalent endocrine tumor, and its incidence is still increasing. The mechanisms of PTC dedifferentiation and malignant progression remain unclear. In this study, we identified AHNAK2 as a key gene in PTC by differential expression analysis among four GEO datasets and validated its overexpression profile by data from the Oncomine, TCGA, and HPA databases and IHC staining analysis. AHNAK2 upregulation significantly correlated with advanced grades, stages, and lymph node events. Survival analysis suggested that AHNAK2 overexpression was coupled with poor overall survival. The immune infiltration analysis by TIMER and CIBERSORT indicated that AHNAK2 expression tightly correlated with the infiltration of diverse immune cell types, especially T cell subtypes. In addition, AHNAK2 is correlated with the expression of other conventional key genes of TC, such as PIK3CA, MAPK1, CTNNB1, and SLC5A5. AHNAK2 may be a novel prognostic marker for PTC.

JAK1 Inhibition Blocks Lethal Immune Hypersensitivity in a Mouse Model of Down Syndrome

Individuals with Down syndrome (DS; trisomy 21) display hyperactivation of interferon (IFN) signaling and chronic inflammation, which could potentially be explained by the extra copy of four IFN receptor (IFNR) genes encoded on chromosome 21. However, the clinical effects of IFN hyperactivity in DS remain undefined. Here, we report that a commonly used mouse model of DS overexpresses IFNR genes and shows hypersensitivity to IFN ligands in diverse immune cell types. When treated repeatedly with a TLR3 agonist to induce chronic inflammation, these animals overexpress key IFN-stimulated genes, induce cytokine production, exhibit liver pathology, and undergo rapid weight loss. Importantly, the lethal immune hypersensitivity and cytokine production and the ensuing pathology are ameliorated by JAK1 inhibition. These results indicate that individuals with DS may experience harmful hyperinflammation upon IFN-inducing immune stimuli, as observed during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pointing to JAK1 inhibition as a strategy to restore immune homeostasis in DS.

Baseline immunity and impact of chemotherapy on immune microenvironment in cervical cancer

BackgroundWe aimed to comprehensively evaluate the immunologic landscape at baseline and upon chemotherapy in cervical cancer. The information should aid ongoing clinical investigations of checkpoint blockade immunotherapies in this disease setting.MethodsA series of 109 cervical carcinoma patients was retrospectively assayed before and after neoadjuvant chemotherapy. Tumour-infiltrating immune markers (CD3, CD4, CD8, CD20, CD56, CD68, PD-1, PD-L1) were assessed by immunohistochemistry. RNA sequencing analysis was performed on matched pre- and post-treatment fresh-frozen tissues.ResultsAt diagnosis, diverse immune cell types including CD20+ B cells, CD3+ T cells, CD56+ natural killer (NK) cells, and CD68+ macrophages were detected in different proportions of cervical carcinoma. Unsupervised hierarchical clustering evidently showed that CD4+ and CD8+ T cell abundance correlated with PD-L1 expression. Based on the immune infiltration patterns, the patients could be stratified into four groups with prognostic relevance, namely, ‘immuno-active’, ‘immuno-medial’, ‘immuno-NK’, and ‘immuno-deficient’. Neoadjuvant chemotherapy was associated with increased CD4, CD8, CD20, and CD56 signals, most prominently in good responders. Transcriptomic data corroborated the improved anticancer immunity and identified immunosuppressive CD200 upregulation following chemotherapeutic intervention.ConclusionsA subset of cervical cancer harbours active immune microenvironment, and chemotherapy treatment may further exert locoregional immunostimulation. Immune checkpoint inhibitors as combination or maintenance therapies warrant future exploration in clinic.

A role for the Sts phosphatases in negatively regulating IFNγ‐mediated production of nitric oxide in monocytes

IntroductionThe atypical Sts phosphatases negatively regulate signaling pathways in diverse immune cell types, with two of their molecular targets being the related kinases Syk and Zap‐70. Mice lacking Sts expression (Sts −/−) are resistant to infection by the live vaccine strain (LVS) of Francisella tularensis. Although the mechanisms underlying the enhanced resistance of Sts −/− mice have not been definitively established, Sts −/− bone marrow‐derived monocytes (BMMs) demonstrate greater clearance of intracellular LVS following ex vivo infection, relative to wild type cells. To determine how the Sts proteins regulate monocyte bactericidal properties, we analyzed responses of infected cells.MethodsMonocyte bacterial clearance was assayed using ex vivo coculture infections followed by colony‐forming unit analysis of intracellular bacteria. Levels of gene expression were quantified by quantitative reverse‐transcription polymerase chain reaction, levels of Nos2 protein levels were quantified by Western blot analysis, and levels of nitric oxide (NO) were quantified directly using the Griess reagent. We characterized monocyte cytokine production via enzyme‐linked immunosorbent assay.ResultsWe demonstrate that Sts −/− monocyte cultures produce elevated levels of interferon‐γ (IFNγ) after infection, relative to wild type cultures. Sts −/− monocytes also demonstrate heightened responsiveness to IFNγ. Specifically, Sts −/− monocytes produce elevated levels of antimicrobial NO following IFNγ stimulation, and this NO plays an important role in LVS restriction. Additional IFNγ‐stimulated genes, including Ip10 and members of the Gbp gene family, also display heightened upregulation in Sts −/− cells. Both Sts‐1 and Sts‐2 contribute to the regulation of NO production, as evidenced by the responses of monocytes lacking each phosphatase individually. Finally, we demonstrate that the elevated production of IFNγ‐induced NO in Sts −/− monocytes is abrogated following chemical inhibition of Syk kinase.ConclusionOur results indicate a novel role for the Sts enzymes in regulating monocyte antibacterial responses downstream of IFNγ.

Targeting STING for cancer therapy

Drug Development Activation of the STING (stimulator of interferon genes) protein by cyclic dinucleotide metabolites plays a critical role in antitumor immunity. The development of synthetic STING agonists is therefore being pursued as a strategy for cancer therapy, but the inherent instability of dinucleotides has limited current efforts. Pan et al. and Chin et al. identified stable STING agonists that act in a “closed” conformation similar to the natural STING ligand, cyclic guanosine monophosphate–adenosine monophosphate (see the Perspective by Gajewski and Higgs). The small molecules can be given orally—an advantage over previously developed STING agonists, which required intratumoral administration. After oral or systemic administration in mice, the agonists activated STING and diverse immune cell types to promote antitumor immunity. These studies represent progress toward clinically viable STING agonists for cancer immunotherapy. Science , this issue p. [eaba6098][1], p. [993][2]; see also p. [921][3] [1]: /lookup/doi/10.1126/science.aba6098 [2]: /lookup/doi/10.1126/science.abb4255 [3]: /lookup/doi/10.1126/science.abc6622

PDIA3 correlates with clinical malignant features and immune signature in human gliomas.

Since therapeutic strategies are limited in gliomas, new molecules or biomarkers are essential for diagnosis and therapy. Here, we investigated expression of protein disulfide isomerase family A member 3 (PDIA3) in gliomas to evaluate its potential as a promising immune target or biomarker. Transcriptome level, genomic profiles and its association with clinical practice from TCGA and CGGA databases were analyzed. All statistical analyses were performed using R project. In gliomas with high PDIA3 expression, somatic mutations showed the correlation with loss of PTEN and amplification of EGFR; meanwhile, in PDIA3 low gliomas, mutations in isocitrate dehydrogenase (IDH) took 80%. Moreover, PDIA3 was found to positively correlate with ESTIMATE scores and diverse infiltrating immune and stromal cell types localizing in tumor microenvironment. PDIA3 was found to be highly correlated with macrophage and T cells based on single cell sequencing. Additionally, PDIA3 was also involved in suppression of anti-tumor immunity via multiple immune regulatory processes. Finally, PDIA3 was observed to correlate with other immune checkpoint inhibitors and associated with inflammation. Our findings identified the significance of PDIA3 in the process of gliomas and demonstrated the potential of PDIA3 as a molecular target in prognosis and immune related treatment of gliomas

Abstract A40: Singling out tumor heterogeneity and chemoresistance in high-grade serous ovarian cancer

Abstract Tumor heterogeneity in high-grade serous ovarian cancer (HGSOC) stems from highly variable copy number changes that lack shared actionable drug targets and contribute to inevitable recurrence and death. To unveil the vast heterogeneity in HGSOC, and understand the molecular changes that occur during chemotherapy, we analyzed single-cell transcriptomes of 49 dissociated HGSOC tumor or ascites specimens, along with six normal postmenopausal fimbria/tuba specimens as controls. This set contains 13 pairs of samples from patients who underwent neoadjuvant chemotherapy, taken before treatment (primary), and after three cycles of standard carboplatin-paclitaxel chemotherapy (interval). Clustering single-cell transcriptomes based on acknowledged cell type markers revealed epithelial cancer cells, as well as diverse stromal and immune cell types. The cell type proportions displayed high variability across HGSOC tumors, intriguingly with lowest tumor purity in patients with short platinum-free interval. To identify the impact of chemotherapy on transcriptional programs, we extracted shared transcriptomic differences in the cancer cells of seven primary-interval pairs. Regardless of the clinical response, three cycles of chemotherapy induced an oxidative stress response program that inhibits apoptosis, while inducing genes involved in MHC II antigen presentation to T helper cells. Next, to study how cell states change during chemotherapy, we ordered the cells in pseudotime based on their transcriptomic similarity, revealing a mixture of primary and interval cells in all but two primary-interval pairs. Furthermore, based on inferred copy number analysis, we estimate that genomic differences contribute variably, between <1% to >20%, to the overall transcriptomic differences between the primary and interval pairs. These results suggest that pre- and post-chemotherapy states are not completely separate and that genomic evolution has a highly variable effect on the state differences, providing support for an intrinsic chemoresistance model with genomic and nongenomic components. To further the understanding of intrinsic resistance, we next focused on patients’ clinical response mechanisms in HGSOC cancer cells. Genes encoding well-known serum markers of HGSOC, WFDC2 and MUC16, were expressed at higher levels in primary specimens of patients with incomplete response, whereas patients with complete response displayed higher expression of genes related to chromatin repression/heterochromatin. Finally, we focused on tumor resectability to understand the transcriptomic patterns underlying HGSOC metastasis. Already prior to chemotherapy, patients with residual disease showed induced FOXO3-driven regulon linked to quiescence, stress resistance, and stemness, whereas patients with no residual disease express increased level of E2F1/DP1-driven regulon linked to BRCAness, high proliferation, and high metabolic rate. Citation Format: Erdogan Pekcan Erkan, Jun Dai, Kaiyang Zhang, Katja Kaipio, Tarja Lamminen, Naziha Mansuri, Lasse Suominen, Amjad Alkodsi, Kaisa Huhtinen, Sakari Hietanen, Johanna Hynninen, Seija Grénman, Olli Carpén, Sampsa Hautaniemi, Anna Vähärautio. Singling out tumor heterogeneity and chemoresistance in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A40.

Cytokines, Masticatory Muscle Inflammation, and Pain: an Update.

Cytokines are proteins secreted by diverse types of immune and non-immune cells and play a role in the communication between the immune and nervous systems. Cytokines include lymphokines, monokines, chemokines, interleukins, interferons, colony stimulating factors, and growth factors. They can be both pro- and anti-inflammatory and have autocrine, paracrine, and endocrine activities. These proteins are involved in initiation and persistence of pain, and the progress of hyperalgesia and allodynia, upon stimulating nociceptive sensory neurons, and inducing central sensitization. The objective of this review is to discuss several types of pro- and anti-inflammatory mediators and their relation with inflammatory pain in masticatory muscles.

VirtualCytometry: a webserver for evaluating immune cell differentiation using single-cell RNA sequencing data.

The immune system has diverse types of cells that are differentiated or activated via various signaling pathways and transcriptional regulation upon challenging conditions. Immunophenotyping by flow and mass cytometry are the major approaches for identifying key signaling molecules and transcription factors directing the transition between the functional states of immune cells. However, few proteins can be evaluated by flow cytometry in a single experiment, preventing researchers from obtaining a comprehensive picture of the molecular programs involved in immune cell differentiation. Recent advances in single-cell RNA sequencing (scRNA-seq) have enabled unbiased genome-wide quantification of gene expression in individual cells on a large scale, providing a new and versatile analytical pipeline for studying immune cell differentiation. We present VirtualCytometry, a web-based computational pipeline for evaluating immune cell differentiation by exploiting cell-to-cell variation in gene expression with scRNA-seq data. Differentiating cells often show a continuous spectrum of cellular states rather than distinct populations. VirtualCytometry enables the identification of cellular subsets for different functional states of differentiation based on the expression of marker genes. Case studies have highlighted the usefulness of this subset analysis strategy for discovering signaling molecules and transcription factors for human T-cell exhaustion, a state of T-cell dysfunction, in tumor and mouse dendritic cells activated by pathogens. With more than 226 scRNA-seq datasets precompiled from public repositories covering diverse mouse and human immune cell types in normal and disease tissues, VirtualCytometry is a useful resource for the molecular dissection of immune cell differentiation. www.grnpedia.org/cytometry.

Functions of Group 2 Innate Lymphoid Cells in Tumor Microenvironment.

Innate lymphoid cells (ILCs), defined as a heterogeneous population of lymphocytes, have received much attention over recent years. They can be categorized into three subsets according to the expression profiles of transcription factors and differing levels of cytokine production. These cells are widely distributed in human organs and tissues, especially in mucosal tissue. The ILCs are involved in various physiological and pathological processes, including inflammation, worm expulsion, autoimmune disease and tumor progression, many of which have been investigated and clarified in recent studies. In the tumor microenvironment, group 2 innate lymphoid cells (ILC2s) have been proved to be able to either promote or inhibit tumor progression by producing different cytokines, recruiting diverse types of immune cells, expressing immunosuppressive molecules and by regulating the expression of certain inflammatory factors. This review summarizes recent research progress on the immunomodulatory functions of ILC2s in the tumor microenvironment and puts forward some perspectives for future study.

Chromatin interaction maps of active cis-regulatory elements in primary human immune cells reveal extensive overlap with disease-associated genetic variants

Abstract Surveys of purified human immune cell types have revealed that common genetic variants have profound effects of gene expression in a highly cell-specific manner. However, it has been challenging to determine the mechanisms behind cell-specific regulatory effects as well as to pinpoint the potentially functional variants in dense haplotype blocks. Here, we performed genome-wide ChIP-Seq and proximity ligation-assisted ChIP-seq assays (HiChIP) for the H3K27ac modification to capture physical interactions between active cis-regulatory elements and their target gene promoters for 5 common and diverse immune cell types from 6 donors. The generated interaction maps identified long-range loops (over 20kb) for more than 90% of active cis-regulatory regions. We found that majority of the cis-regulatory interactions were highly cell-specific, which in turn correlated with cell-specific transcription factor binding motifs and gene expression patterns. Nearly 10% of expression quantitative trait loci (eQTLs), including disease-associated eQTLs and GWAS SNPs, were located at active cis-regulatory regions that interacted with the target genes of eQTLs (eGenes), thus allowing us to narrow down potentially functional/causative QTLs. Majority of cis-eQTLs that are specific to only a single cell type overlapped cis-regulatory elements that showed interactions with the promoter of their target eGenes only in that specific cell type. Our study thus provides a comprehensive interaction map of active regulatory elements for each of the 5 immune cell types across multiple donors and highlights the cell type-specificity of potentially functional variants and interactions linking them to genes in human disease.

Cell-specific immune-modulation of cadmium on murine macrophages and mast cell lines in vitro.

Toxic trace metals are widespread contaminants that are potentially immunotoxic even at environmentally low exposure levels. They can modulate the immunity to infections, e.g., in wildlife species living in contaminated areas. The diverse immune cell types can be differentially affected by the exposure leading to the modulation of specific protective mechanisms. Macrophages and mast cells, part of the innate immune system, trigger immune responses and perform particular effector functions. The present study compared toxicological and functional effects of cadmium in two models of murine macrophages (RAW264.7 and NR8383 cell lines) and two models of murine mast cells (MC/9 and RBL-2H3 cell lines). Cadmium was selected as a model compound because its known potential to induce reactive oxygen species and its relevance as an environmental contaminant. Mechanisms of toxicity, such as redox imbalance and apoptosis induction were measured in stationary cells, while functional outcome effects were measured in activated cells. Cadmium-depleted glutathione antioxidant in all four cell lines tested although reactive oxygen species was not significantly increased. Mast cells had full dose-response depletion of glutathione below cytotoxic levels while in macrophages the depletion was not complete. Functional endpoints tumour necrosis factor-alpha and nitrite production in lipopolysaccharide-activated macrophages were increased by cadmium exposure. In contrast, mast cell lipopolysaccharide-induced tumour necrosis factor-alpha and IgE-mediated histamine release were reduced by cadmium. These data indicate potentially differential effects of cadmium among murine innate immune cell types, where mast cells would be more susceptible to oxidative stress and their function might be at a higher risk to be modulated compared to macrophages.

MTOR Signaling pathway as a master regulator of memory CD8+ T-cells, Th17, and NK cells development and their functional properties.

The mammalian target of rapamycin (mTOR) is a member of the evolutionary phosphatidylinositol kinase-related kinases (PIKKs). mTOR plays a pivotal role in the regulation of diverse aspects of cellular physiology such as body metabolism, cell growth, protein synthesis, cell size, autophagy, and cell differentiation. Immunologically, mTOR has a fundamental part in controlling and shaping diverse functions of innate and adaptive immune cells, in particular, T-cell subsets differentiation, survival, and metabolic reprogramming to ultimately regulate the fate of diverse immune cell types. Researchers report that rapamycin, a selective mTOR inhibitor, and immunosuppressive agent, has surprising immunostimulatory effects on inducing both quantitative and qualitative aspects of virus-specific memory CD8+ T-cells differentiation and homeostasis in a T-cell-intrinsic manner. The mTOR signaling pathway also plays a critical role in dictating the outcome of regulatory T cells (Treg), T helper 17 (Th17) cells, and natural killer (NK) cells proliferation and maturation, as well as the effector functions and cytotoxic properties of NK cells. Manipulation of mTOR activity is a critical therapeutic approach for pharmacological agents that seek to inhibit mTOR. This approach should enhance specific memory CD8 + T-cells responses and induce fully functional effector properties of NK cells to provoke their antitumor and antiviral activities.

Prognostic Implications of Heterogeneity in Intra-tumoral Immune Composition for Recurrence in Early Stage Lung Cancer.

Background: Studies in the past have identified selected immune cells that associate with different clinical outcomes in non-small cell lung cancer (NSCLC). Considering the fact that immune responses are heterogenous and that the clinical outcome could be influenced by the interplay of various immune cell types, it is imperative to evaluate multiple intra-tumoral immune cell types in the same set of patients.Objective: To evaluate the individual and combined effects of diverse intra-tumoral immune cell types on recurrence after complete surgical resection in early stage lung adenocarcinoma.Methods: We obtained NCBI GEO datasets for lung adenocarcinoma, the most prevalent histological subtype of NSCLC and re-analyzed the gene expression data of 292 patients with early stage cancer (IA/IB). CIBERSORT was used to resolve 22 immune cell types from the tumor transcriptomes. Survival analysis was carried out to assess the effect of immune cell types and genes associated with recurrence.Results: Out of the 22 cell types, a high proportion of Tregs and monocyte-macrophages in the tumors were associated with significantly increased probability of recurrence. Conversely, increased proportion of non-Treg CD4+ T cells and plasma cells were associated with a lower probability of recurrence. The higher expression of CCL20 (which can direct the migration of cells of B cell lineage), XCL1 (associated with prototypical Th1 responses) and the immunoglobulin chains IGHV4.34 and IGLV6.57 were associated with a significantly lower probability of recurrence. Importantly, the intra-tumoral immune phenotype comprising these four cell types varied among patients and differentially associated with recurrence depending on net levels of positive and negative prognostic factors. Despite a high level of intra-tumoral plasma cells, a concomitant high level of monocyte-macrophages reduced the freedom from recurrence from ~80 to ~50% at 80 months (p < 0.05). Furthermore, stratification of the patients on the basis of a score estimated from the levels of four cell types enabled the identification of patients with significantly increased probability of recurrence (~50%) after surgery.Significance: Our analysis suggests that concomitant levels of macrophages and plasma cells, in addition to the T regs and non-TregCD4+ T cells in tumors can identify patients with early stage lung cancer at greater risk of recurrence.

Essential Domain-Dependent Roles Within Soluble IgG for in vivo Superantigen Properties of Staphylococcal Protein A: Resolving the B-Cell Superantigen Paradox

Staphylococcus aureus is a common commensal and frequent opportunistic pathogen that causes invasive infections that often recur. Co-evolution with the host has led to the development of toxins that affect diverse immune cell types. Recent reports have highlighted the contributions of staphylococcal protein A (SpA). This small oligomeric secreted protein contains 4–5 homologous domains with two distinct immunoglobulin-binding sites; one for IgG Fc domains, while a separate site binds an evolutionarily conserved surface on Fab encoded by VHIII clan related genes. The Fab-binding site has been implicated in in vivo supraclonal VHIII-BCR targeted B-cell depletion by an activation induced death pathway. Yet the concept of a superantigen for B lymphocytes poses a seeming paradox. Unlike TCR that are expressed only in a membrane-associated form, BCR are expressed in both a membrane BCR form and in secreted Ig forms, which permeate virtually every part of the body at high levels. We therefore asked, why circulating immunoglobulin do not block the superantigen properties of SpA? Herein, we show that soluble IgG molecules are not in vivo inhibitors of these B-cell superantigen effects but are instead essential for potentiating these properties. We also show that the Fc subclass of circulating IgG is an indirect critical determinant of the B-cell superantigen effect. In contrast, host FcγR and complement are not required for SpA mediated in vivo B-cell depletion. Unexpectedly, after VHIII-IgG2a pretreatment SpA challenge resulted in fatal anaphylactic reactions, which we speculate may have involved FcγR interactions with mast cells and basophils. Cumulatively, our findings illuminate a cunning and potent molecular strategy by which a bacterial toxin effectively confounds the contributions of host B-lymphocytes to immune defenses.

Control of Germinal Center Responses by T-Follicular Regulatory Cells.

Regulatory T-cells (Treg cells), expressing the transcription factor Foxp3, have an essential role in the control of immune homeostasis. In order to control diverse types of immune responses Treg cells must themselves show functional heterogeneity to control different types of immune responses. Recent advances have made it clear that Treg cells are able to mirror the homing capabilities of known T-helper subtypes such as Th1, Th2, Th17, and T-follicular helper cells (Tfh), allowing them to travel to the sites of inflammation and deliver suppression in situ. One of the more recent discoveries in this category is the description of T-follicular regulatory (Tfr) cells, a specialized subset of Treg cells that control Tfh and resulting antibody responses. In this review we will discuss recent advances in our understanding of Tfr biology and the role of both Tfr and activated extra-follicular Tregs (eTreg) in the control of humoral immunity.

Integrative Genome-Wide Analysis of Long Noncoding RNAs in Diverse Immune Cell Types of Melanoma Patients.

Genome-wide identification and characterization of long noncoding RNAs (lncRNA) in individual immune cell lineages helps us better understand the driving mechanisms behind melanoma and advance personalized patient treatment. To elucidate the transcriptional landscape in diverse immune cell types of peripheral blood cells (PBC) in stage IV melanoma, we used whole transcriptome RNA sequencing to profile lncRNAs in CD4+, CD8+, and CD14+ PBC from 132 patient samples. Our integrative computational approach identified 27,625 expressed lncRNAs, 2,744 of which were novel. Both T cells (i.e., CD4+ and CD8+ PBC) and monocytes (i.e., CD14+ PBC) exhibited differential transcriptional expression profiles between patients with melanoma and healthy subjects. Cis- and trans-level coexpression analysis suggested that lncRNAs are potentially involved in many important immune-related pathways and the programmed cell death receptor 1 checkpoint pathways. We also identified nine gene coexpression modules significantly associated with melanoma status, all of which were significantly enriched for three mRNA translation processes. Age and melanoma traits closely correlated with each other, implying that melanoma contains age-associated immune changes. Our computational prediction analysis suggests that many cis- and trans-regulatory lncRNAs could interact with multiple transcriptional and posttranscriptional regulatory elements in CD4+, CD8+, and CD14+ PBC, respectively. These results provide novel insights into the regulatory mechanisms involving lncRNAs in individual immune cell types in melanoma and can help expedite cell type-specific immunotherapy treatments for such diseases.Significance: These findings elucidate melanoma-associated changes to the noncoding transcriptional landscape of distinct immune cell classes, thus providing cell type-specific guidance to targeted immunotherapy regimens. Cancer Res; 78(15); 4411-23. ©2018 AACR.

Disease-specific regulation of gene expression in a comparative analysis of juvenile idiopathic arthritis and inflammatory bowel disease

BackgroundThe genetic and immunological factors that contribute to differences in susceptibility and progression between sub-types of inflammatory and autoimmune diseases continue to be elucidated. Inflammatory bowel disease and juvenile idiopathic arthritis are both clinically heterogeneous and known to be due in part to abnormal regulation of gene activity in diverse immune cell types. Comparative genomic analysis of these conditions is expected to reveal differences in underlying genetic mechanisms of disease.MethodsWe performed RNA-Seq on whole blood samples from 202 patients with oligoarticular, polyarticular, or systemic juvenile idiopathic arthritis, or with Crohn’s disease or ulcerative colitis, as well as healthy controls, to characterize differences in gene expression. Gene ontology analysis combined with Blood Transcript Module and Blood Informative Transcript analysis was used to infer immunological differences. Comparative expression quantitative trait locus (eQTL) analysis was used to quantify disease-specific regulation of transcript abundance.ResultsA pattern of differentially expressed genes and pathways reveals a gradient of disease spanning from healthy controls to oligoarticular, polyarticular, and systemic juvenile idiopathic arthritis (JIA); Crohn’s disease; and ulcerative colitis. Transcriptional risk scores also provide good discrimination of controls, JIA, and IBD. Most eQTL are found to have similar effects across disease sub-types, but we also identify disease-specific eQTL at loci associated with disease by GWAS.ConclusionJIA and IBD are characterized by divergent peripheral blood transcriptomes, the genetic regulation of which displays limited disease specificity, implying that disease-specific genetic influences are largely independent of, or downstream of, eQTL effects.