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Understanding the phenotypic and transcriptional signature of immunoglobulin E (IgE)–producing cells is fundamental to plasma cell (PC) biology and development of therapeutic interventions for allergy. Here, using a mouse model of intranasal house dust mite (HDM) exposure, we showed that short-lived IgE PCs emerge in lung draining lymph nodes (dLNs) during early exposure (<3 weeks) and long-lived IgE PCs accumulate in the bone marrow (BM) with prolonged exposure (>7 weeks). IgE PCs had distinct surface and gene expression profiles in these different tissues compared with other Ig isotypes. IgE BMPCs up-regulated genes associated with prosurvival and BM homing, whereas IgE dLN PCs expressed genes associated with recent class switching and differentiation. IgE PCs also exhibited higher expression of endoplasmic reticulum (ER) stress and protein coding genes and higher antibody secretion rate when compared with IgG1. Overall, this study highlights the unique developmental path and transcriptional signature of short-lived and long-lived IgE PCs. Editor's summary: Immunoglobulin E (IgE)–mediated allergic diseases can be fatal, yet our understanding of IgE-producing plasma cells (PCs) is limited. Vecchione et al. used a transgenic mouse reporter strain to characterize IgE PCs during chronic house dust mite exposure. IgE PCs were transcriptionally and phenotypically unique compared with other immunoglobulin isotypes, with higher levels of endoplasmic reticulum stress and increased antibody production. Short-lived IgE PCs appeared early in the lung draining lymph nodes post–allergen exposure, whereas long-lived bone marrow (BM) IgE PCs were not detected until much later. IgE BMPCs from humans with allergy also had unique transcriptional signatures. These findings demonstrate that IgE PCs are developmentally, transcriptionally, and functionally unique. —Hannah Isles [ABSTRACT FROM AUTHOR]

Background: Nasal epithelial cells are important regulators of barrier function and immune signaling; however, in allergic rhinitis (AR) these functions can be disrupted by inflammatory mediators. We aimed to better discern AR disease mechanisms using transcriptome data from nasal brushing samples from individuals with and without AR. Methods: Data were drawn from a feasibility study of individuals with and without AR to Timothy grass and from a clinical trial evaluating 16 weeks of treatment with the following: dupilumab, a monoclonal antibody that binds interleukin (IL)‐4Rα and inhibits type 2 inflammation by blocking signaling of both IL‐4/IL‐13; subcutaneous immunotherapy with Timothy grass (SCIT), which inhibits allergic responses through pleiotropic effects; SCIT + dupilumab; or placebo. Using nasal brushing samples from these studies, we defined distinct gene signatures in nasal tissue of AR disease and after nasal allergen challenge (NAC) and assessed how these signatures were modulated by study drug(s). Results: Treatment with dupilumab (normalized enrichment score [NES] = −1.73, p =.002) or SCIT + dupilumab (NES = −2.55, p <.001), but not SCIT alone (NES = +1.16, p =.107), significantly repressed the AR disease signature. Dupilumab (NES = −2.55, p <.001), SCIT (NES = −2.99, p <.001), and SCIT + dupilumab (NES = −3.15, p <.001) all repressed the NAC gene signature. Conclusion: These results demonstrate type 2 inflammation is an important contributor to the pathophysiology of AR disease and that inhibition of the type 2 pathway with dupilumab may normalize nasal tissue gene expression. [ABSTRACT FROM AUTHOR]

An increasing amount of evidence suggests that canonical pathways and standard molecular signature databases are incomplete and inadequate to model the complex behavior of cell physiology and pathology. Yet, many Gene Set Analysis (GSA) studies still rely on these databases to identify disease biomarkers and molecular mechanisms within a specific cell context. While tremendous effort has been invested in developing GSA tools, there is limited number of studies focusing on de novo assembly of context-specific gene sets as opposed to simply applying GSA using the standard gene set database.

The common γ chain (γc; IL-2RG) is a subunit of the interleukin (IL) receptors for the γc cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The lack of appropriate neutralizing antibodies recognizing IL-2RG has made it difficult to thoroughly interrogate the role of γc cytokines in inflammatory and autoimmune disease settings. Here, we generated a γc cytokine receptor antibody, REGN7257, to determine whether γc cytokines might be targeted for T cell–mediated disease prevention and treatment. Biochemical, structural, and in vitro analysis showed that REGN7257 binds with high affinity to IL-2RG and potently blocks signaling of all γc cytokines. In nonhuman primates, REGN7257 efficiently suppressed T cells without affecting granulocytes, platelets, or red blood cells. Using REGN7257, we showed that γc cytokines drive T cell–mediated disease in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis by affecting multiple aspects of the pathogenic response. We found that our xenogeneic GVHD mouse model recapitulates hallmarks of acute and chronic GVHD, with T cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. Our findings indicate that γc cytokines contribute to GVHD and aplastic anemia pathology by promoting these characteristic features. By demonstrating that broad inhibition of γc cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of γc cytokines as key drivers of pathogenic T cell responses, offering a potential strategy for the management of T cell–mediated diseases. Curbing counterproductive cytokines: The common γ chain (γc; IL-2RG) is a component of cytokine receptors specific to the γc cytokine family that includes IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Studies of the γc cytokines have been constrained by the lack of a neutralizing antibody that can recognize IL-2RG. Le Floc'h et al. describe the generation and characterization of REGN7257, a monoclonal antibody specific to IL-2RG. In vitro studies confirmed that REGN7257 binds with high affinity to IL-2RG and specifically blocks γc cytokine signaling. Treatment of nonhuman primates with REGN7257 suppressed NK cells and T cells without affecting granulocytes, erythrocytes, or platelets. Interestingly, REGN7257 curbed pathogenic responses in mouse models of allogeneic and xenogeneic graft-versus-host-disease, immune aplastic anemia, and multiple sclerosis, thus confirming the critical role of the γc cytokines in these immune mediated disorders.—CNF [ABSTRACT FROM AUTHOR]

The inference of transcriptional networks that regulate transitions into physiological or pathological cellular states remains a central challenge in systems biology. A mesenchymal phenotype is the hallmark of tumour aggressiveness in human malignant glioma, but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Here we show that reverse-engineering and an unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors (C/EBPβ and STAT3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPβ and STAT3 reprograms neural stem cells along the aberrant mesenchymal lineage, whereas elimination of the two factors in glioma cells leads to collapse of the mesenchymal signature and reduces tumour aggressiveness. In human glioma, expression of C/EBPβ and STAT3 correlates with mesenchymal differentiation and predicts poor clinical outcome. These results show that the activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotvoic state in cancer cells., High-grade gliomas (HGGs) are the most common brain tumours in humans and are essentially incurable (1). The defining hallmarks of the aggressiveness of glioblastoma multiforme (GBM) are local invasion and [...]

Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL (1). Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-κB transcription complex (2). However, except for a small fraction of cases (3), it remains unclear whether NF-κB activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event. Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3, also called A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 (TAK1) and TNFRSF11A (RANK)) regulators of NF-κB. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-κB responses, is most commonly affected, with ~30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumour suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-κB. Thus, our results demonstrate that NF-κB activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-κB responses., DLBCL represents a heterogeneous disease in terms of genetic, phenotypic and clinical features. Accordingly, genome-wide expression profile studies revealed the existence of several DLBCL categories, reflecting their origin from discrete [...]

Sequelae of unrestrained IL-36 signaling: The IL-36 receptor integrates signals from three proinflammatory IL-36 agonist ligands opposed by one natural antagonist (IL-36Ra). Hovhannisyan et al. developed mice humanized for the extracellular portion of IL-36R and the IL-36 agonists (α, β, and γ) to evaluate anti-inflammatory treatment using antibodies blocking the human IL-36R. The mouse version of IL-36Ra retained by these mice is a weaker inhibitor at the human IL-36R than its human counterpart, leaving these mice susceptible to enhanced skin and intestinal inflammation after epithelial barrier insults. Antibodies blocking the IL-36R or the shared p40 subunit of IL-12/IL-23 interrupted an overlapping set of proinflammatory circuits in these mice, indicating that IL-36R–targeting therapeutics are candidates to treat some of the same human diseases responsive to inhibition of the IL-23/IL-17 axis. Deficiency in interleukin-36R (IL-36R) antagonist caused by loss-of-function mutations in IL-36RN leads to DITRA (deficiency of IL-36 receptor antagonist), a rare inflammatory human disease that belongs to a subgroup of generalized pustular psoriasis (GPP). We report a functional genetic mouse model of DITRA with enhanced IL-36R signaling analogous to that observed in patients with DITRA, which provides new insight into our understanding of the IL-36 family of molecules in regulating barrier integrity across multiple tissues. Humanized DITRA-like mice displayed increased skin inflammation in a preclinical model of psoriasis, and in vivo blockade of IL-36R pathway using anti-human IL-36R antibody ameliorated imiquimod-induced skin pathology as both prophylactic and therapeutic treatments. Deeper characterization of the humanized DITRA-like mice revealed that deregulated IL-36R signaling promoted tissue pathology during intestinal injury and led to impairment in mucosal restoration in the repair phase of chronic dextran sulfate sodium (DSS)–induced colitis. Blockade of IL-36R pathway significantly ameliorated DSS-induced intestinal inflammation and rescued the inability of DITRA-like mice to recover from mucosal damage in vivo. Our results indicate a central role for IL-36 in regulating proinflammatory responses in the skin and epithelial barrier function in the intestine, suggesting a new therapeutic potential for targeting the IL-36R axis in psoriasis and at the later stages of intestinal pathology in inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Background: Dupilumab, a fully human monoclonal antibody that binds IL‐4Rα and inhibits signaling of both IL‐4 and IL‐13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis, and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL‐4 and IL‐13 in type 2 inflammation and report dupilumab mechanisms of action. Methods: Using primary cell assays and a mouse model of house dust mite–induced asthma, we compared IL‐4 vs IL‐13 vs IL‐4Rα blockers. Results: Intranasal administration of either IL‐4 or IL‐13 confers an asthma‐like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head‐to‐head studies, either IL‐4 or IL‐13 inhibition to dual IL‐4/IL‐13 inhibition, we demonstrate that blockade of both IL‐4 and IL‐13 is required to broadly block type 2 inflammation, which translates to protection from allergen‐induced lung function impairment. Notably, only dual IL‐4/IL‐13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils, contributes to disease pathology. Conclusions: Overall, these data support IL‐4 and IL‐13 as key drivers of type 2 inflammation and help provide insight into the therapeutic mechanism of dupilumab, a dual IL‐4/IL‐13 blocker, in multiple type 2 diseases. [ABSTRACT FROM AUTHOR]

The ability of a transcription factor (TF) to regulate its targets is modulated by a variety of genetic and epigenetic mechanisms, resulting in highly context-dependent regulatory networks. However, high-throughput methods for the identification of proteins that affect TF activity are still largely unavailable. Here we introduce an algorithm, modulator inference by network dynamics (MINDy), for the genome-wide identification of post-translational modulators of TF activity within a specific cellular context. When used to dissect the regulation of MYC activity in human B lymphocytes, the approach inferred novel modulators of MYC function, which act by distinct mechanisms, including protein turnover, transcription complex formation and selective enzyme recruitment. MINDy is generally applicable to study the post-translational modulation of mammalian TFs in any cellular context. As such it can be used to dissect context-specific signaling pathways and combinatorial transcriptional regulation. [ABSTRACT FROM AUTHOR]

The computational identification of oncogenic lesions is still a key open problem in cancer biology. Although several methods have been proposed, they fail to model how such events are mediated by the network of molecular interactions in the cell. In this paper, we introduce a systems biology approach, based on the analysis of molecular interactions that become dysregulated in specific tumor phenotypes. Such a strategy provides important insights into tumorigenesis, effectively extending and complementing existing methods. Furthermore, we show that the same approach is highly effective in identifying the targets of molecular perturbations in a human cellular context, a task virtually unaddressed by existing computational methods. To identify interactions that are dysregulated in three distinct non-Hodgkin’s lymphomas and in samples perturbed with CD40 ligand, we use the B-cell interactome (BCI), a genome-wide compendium of human B-cell molecular interactions, in combination with a large set of microarray expression profiles. The method consistently ranked the known gene in the top 20 (0.3%), outperforming conventional approaches in 3 of 4 cases. [ABSTRACT FROM AUTHOR]

The article examines the impact of the IL-4-IL-4Rα axis on olfactory neuroimmune signaling and its role in inducing loss of smell. Through studies on mice and human translational data, the research reveals that IL-4 disrupts olfactory sensory neurons' responsiveness to odors, leading to neuroinflammation and immune responses in the olfactory epithelium. The findings suggest that IL-4-IL-4Rα signaling mediates neuroimmune crosstalk, driving olfactory dysfunction in conditions like chronic rhinosinusitis with nasal polyps. The study, conducted by researchers from Sanofi and Regeneron Pharmaceuticals, provides insights into potential therapeutic strategies for addressing olfactory dysfunction and related conditions. [Extracted from the article]

Summary: Self-renewal and proliferation of neural stem cells and the decision to initiate neurogenesis are crucial events directing brain development. Here we show that the ubiquitin ligase Huwe1 operates upstream of the N-Myc-DLL3-Notch pathway to control neural stem cell activity and promote neurogenesis. Conditional inactivation of the Huwe1 gene in the mouse brain caused neonatal lethality associated with disorganization of the laminar patterning of the cortex. These defects stemmed from severe impairment of neurogenesis associated with uncontrolled expansion of the neural stem cell compartment. Loss- and gain-of-function experiments in the mouse cortex demonstrated that Huwe1 restrains proliferation and enables neuronal differentiation by suppressing the N-Myc-DLL3 cascade. Notably, human high-grade gliomas carry focal hemizygous deletions of the X-linked Huwe1 gene in association with amplification of the N-myc locus. Our results indicate that Huwe1 balances proliferation and neurogenesis in the developing brain and that this pathway is subverted in malignant brain tumors. [Copyright &y& Elsevier]