Immunoglobulin-coating patterns reveal altered humoral responses to gut bacteria in pediatric cow milk allergies.

Background: Pediatric cow milk allergies (CMA) can occur in immunoglobulin (Ig) E and non-IgE-mediated forms. Unlike IgE-mediated allergies, the mechanisms of disease pathogenesis in non-IgE-mediated food allergy and an association with microbiome has not been well established. Previous studies have identified the presence of altered humoral responses to gut bacteria in IgE mediated allergies.

Circulating interleukin-33 levels in obesity and type 2 diabetes: a systematic review and meta-analysis.

Obesity and type 2 diabetes (T2D) are increasingly prevalent worldwide, and there is a critical need for novel interventions. Interleukin-33 (IL-33), an anti-inflammatory cytokine that regulates metabolism, is a promising biomarker for these conditions. The goal of this systematic review and meta-analysis is to examine the role of IL-33 in obesity and T2D, assessing its potential in predicting disease progression.

IL-2 amplifies quantitative TCR signalling inputs to drive Th1 and Th2 differentiation.

The activation of CD4+ T-cells in a T cell receptor (TCR)-dependent antigen-specific manner is a central characteristic of the adaptive immune response. In addition to ensuring that CD4+ T-cells recognise their cognate antigen during activation, TCR-mediated signalling can also direct the outcome of differentiation. In both in vivo and in vitro model systems, strong TCR signalling has been demonstrated to drive Th1 differentiation, whereas weak TCR signalling drives Th2 responses.

The molecular landscape of sepsis severity in infants: enhanced coagulation, innate immunity, and T cell repression.

Introduction: Sepsis remains a major cause of mortality and morbidity in infants. In recent years, several gene marker strategies for the early identification of sepsis have been proposed but only a few have been independently validated for adult cohorts and applicability to infant sepsis remains unclear. Biomarkers to assess disease severity and risks of shock also represent an important unmet need.

Applications of Genome-Editing Technologies for Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells by the immune system. Although conventional therapeutic modalities, such as insulin injection, remain a mainstay, recent years have witnessed the emergence of novel treatment approaches encompassing immunomodulatory therapies, such as stem cell and β-cell transplantation, along with revolutionary gene-editing techniques. Notably, recent research endeavors have enabled the reshaping of the T-cell repertoire, leading to the prevention of T1D development.

Dendritic cell activation and screening for key molecular signatures required for the induction of allergic responses.

The chain of events that leads to the sensitization of the immune system to environmental antigens, resulting in the onset of allergic disease, has been studied in great detail over the past 30 years. However, during this time, the rate of allergic diseases has increased exponentially, indicating the need to concentrate our studies on host-environmental factors that contribute to the onset of disease. Monocyte-derived dendritic cells (DCs) play a key role in driving localized and systemic immune responses.

Gut microbial influences on the adaptive immune system and the development of cow milk allergy.

Allergic diseases constitute significant health and economic issues in both developed and developing nations, with epidemiological studies demonstrating a rapid increase in the global prevalence of food allergy among the pediatric population. Cow milk protein allergy (CMPA), one of the most common forms of food allergies observed in early childhood, affects between 2%-6% of infants and children under 3 years of age. CMPA can present as either an IgE-mediated atopic allergy or a non-IgE mediated allergic response.

Asthma and the Missing Heritability Problem: Necessity for Multiomics Approaches in Determining Accurate Risk Profiles.

Asthma is ranked among the most common chronic conditions and has become a significant public health issue due to the recent and rapid increase in its prevalence. Investigations into the underlying genetic factors predict a heritable component for its incidence, estimated between 35% and 90% of causation. Despite the application of large-scale genome-wide association studies (GWAS) and admixture mapping approaches, the proportion of variants identified accounts for less than 15% of the observed heritability of the disease.

Microbial Dysbiosis Tunes the Immune Response Towards Allergic Disease Outcomes.

The hygiene hypothesis has been popularized as an explanation for the rapid increase in allergic disease observed over the past 50 years. Subsequent epidemiological studies have described the protective effects that in utero and early life exposures to an environment high in microbial diversity have in conferring protective benefits against the development of allergic diseases. The rapid advancement in next generation sequencing technology has allowed for analysis of the diverse nature of microbial communities present in the barrier organs and a determination of their role in the induction of allergic disease.

Functional Characterization of the Variant p.E60Q in Non-Syndromic Hearing Loss Patients.

Hereditary hearing loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children, of which 70% is inherited in an autosomal recessive pattern. The long tradition of consanguinity among the Qatari population has increased the prevalence of HHL, which negatively impacts the quality of life. Here, we functionally validated the pathogenicity of the c.

Transcriptomic profile investigations highlight a putative role for NUDT16 in sepsis.

Sepsis is an aberrant systemic inflammatory response mediated by the acute activation of the innate immune system. Neutrophils are important contributors to the innate immune response that controls the infection, but harbour the risk of collateral tissue damage such as thrombosis and organ dysfunction. A better understanding of the modulations of cellular processes in neutrophils and other blood cells during sepsis is needed and can be initiated via transcriptomic profile investigations.

Transcriptome and Literature Mining Highlight the Differential Expression of ERLIN1 in Immune Cells during Sepsis.

Sepsis results from the dysregulation of the host immune system. This highly variable disease affects 19 million people globally, and accounts for 5 million deaths annually. In transcriptomic datasets curated from public repositories, we observed a consistent upregulation (3.

Flow-Cytometry Platform for Intracellular Detection of FVIII in Blood Cells: A New Tool to Assess Gene Therapy Efficiency for Hemophilia A.

Detection of factor VIII (FVIII) in cells by flow cytometry is controversial, and no monoclonal fluorescent antibody is commercially available. In this study, we optimized such an assay and successfully used it as a platform to study the functional properties of phosphoglycerate kinase (PGK)-FVIII lentiviral vector-transduced cells by directly visualizing FVIII in cells after different gene transfer conditions. We could measure cellular stress parameters after transduction by correlating gene expression and protein accumulation data.

Quantifying in situ adaptive immune cell cognate interactions in humans.

Two-photon excitation microscopy (TPEM) has revolutionized the understanding of adaptive immunity. However, TPEM usually requires animal models and is not amenable to the study of human disease. The recognition of antigen by T cells requires cell contact and is associated with changes in T cell shape.

Studying Dendritic Cell-T Cell Interactions Under In Vivo Conditions.

The interactions between dendritic cells and T cells during the initiation of an adaptive immune response underpins one of the most important checkpoints in ensuring that the correct immune response is induced, in order to direct the development of immune tolerance or to mount an immune response against pathogenic organisms. The advent of two-photon intravital imaging allows us to directly study the interactions between dendritic cells and T cells as they occur under physiological conditions, greatly improving our understanding of the dynamic relationship that occurs during T cell activation and expanding our knowledge of how the adaptive immune system is regulated during both priming and memory responses. Here, we describe a technique for the in vivo analysis of the interactions between either CD4+ or CD8+ T cells and dendritic cells as they occur in the popliteal lymph nodes of live mice.

Allergen-Induced CD4+ T Cell Cytokine Production within Airway Mucosal Dendritic Cell-T Cell Clusters Drives the Local Recruitment of Myeloid Effector Cells.

Allergic asthma develops in the mucosal tissue of small bronchi. At these sites, local cytokine production by Th2/Th17 cells is believed to be critical for the development of tissue eosinophilia/neutrophilia. Using the mouse trachea as a relevant model of human small airways, we performed advanced in vivo dynamic and in situ static imaging to visualize individual cytokine-producing T cells in the airway mucosa and to define their immediate cellular environment.

TCR Signal Strength Alters T-DC Activation and Interaction Times and Directs the Outcome of Differentiation.

The ability of CD4+ T cells to differentiate into effector subsets underpins their ability to shape the immune response and mediate host protection. During T cell receptor-induced activation of CD4+ T cells, both the quality and quantity of specific activatory peptide/MHC ligands have been shown to control the polarization of naive CD4+ T cells in addition to co-stimulatory and cytokine-based signals. Recently, advances in two--photon microscopy and tetramer-based cell tracking methods have allowed investigators to greatly extend the study of the role of TCR signaling in effector differentiation under in vivo conditions.

Immune homeostasis enforced by co-localized effector and regulatory T cells.

FOXP3(+) regulatory T cells (Treg cells) prevent autoimmunity by limiting the effector activity of T cells that have escaped thymic negative selection or peripheral inactivation. Despite the information available about molecular factors mediating the suppressive function of Treg cells, the relevant cellular events in intact tissues remain largely unexplored, and whether Treg cells prevent activation of self-specific T cells or primarily limit damage from such cells has not been determined. Here we use multiplex, quantitative imaging in mice to show that, within secondary lymphoid tissues, highly suppressive Treg cells expressing phosphorylated STAT5 exist in discrete clusters with rare IL-2-positive T cells that are activated by self-antigens.

Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance.

Improving the functional avidity of effector T cells is critical in overcoming inhibitory factors within the tumor microenvironment and eliciting tumor regression. We have found that Cish, a member of the suppressor of cytokine signaling (SOCS) family, is induced by TCR stimulation in CD8(+) T cells and inhibits their functional avidity against tumors. Genetic deletion of Cish in CD8(+) T cells enhances their expansion, functional avidity, and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors.

NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ-IL-27 axis.

IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis, and arthritis. Here, we demonstrate using IFN-γ(-/-) mice repleted with IFN-γ +/+: NK cells that innate production of IFN-γ from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit that limits autoimmunity.

T-cell-receptor-dependent signal intensity dominantly controls CD4(+) T cell polarization In Vivo.

Polarization of effector CD4(+) T cells can be influenced by both antigen-specific signals and by pathogen- or adjuvant-induced cytokines, with current models attributing a dominant role to the latter. Here we have examined the relationship between these factors in shaping cell-mediated immunity by using intravital imaging of CD4(+) T cell interactions with dendritic cells (DCs) exposed to polarizing adjuvants. These studies revealed a close correspondence between strength of T cell receptor (TCR)-dependent signaling and T helper 1 (Th1) versus Th2 cell fate, with antigen concentration dominating over adjuvant in controlling T cell polarity.

Mucosal trapping and degradation of Nippostrongylus brasiliensis occurs in the absence of STAT6.

Hookworms represent a major infectious burden globally, especially in developing countries. The murine hookworm Nippostrongylus brasiliensis is normally cleared in a manner dependent on IL-13, IL4-R and STAT6 signalling. Here we have used STAT6-deficient animals to model a non-resistant population and describe 2 novel STAT6-independent processes for the clearance of N.

Immature murine NKT cells pass through a stage of developmentally programmed innate IL-4 secretion.

We assessed the production of the canonical Th2 cytokine IL-4 by NKT cells directly in vivo using IL-4-substituting strains of reporter mice that provide faithful and sensitive readouts of cytokine production without the confounding effects of in vitro stimulation. Analysis in naïve animals revealed an "innate" phase of IL-4 secretion that did not need to be triggered by administration of a known NKT cell ligand. This secretion was by immature NKT cells spanning Stage 1 of the maturation process in the thymus (CD4(+) CD44(lo) NK1.