Science Immunology

BackgroundGastroenteric tract requires robust tolerogenic mechanisms to tolerize foreign antigens like foods and microbiota. This is critical to establish the immune homeostasis, which upon disruption, might contribute to a plethora of atopic disorders, including food allergy and eosinophilic esophagitis (EOE). Recently, there was a new subset of tolerizing dendritic cells (tolDCs), PRDM16 tolDC, discovered in the gut of mice and humans, which confers protection against food allergy. Whether an ...

BackgroundInfluenza vaccination and bacterial colonization both shape immunity in the respiratory tract, yet their combined impact on the human lung mucosa remains poorly understood. Secondary bacterial pneumonia following influenza infection is a leading cause of mortality, underscoring the need to define how vaccines and microbes intersect at the airway interface. MethodsUsing the Experimental Human Pneumococcal Challenge (EHPC) model, we examined how intramuscular inactivated (TIV) and nasal...

Sjogrens disease (SjD) is a chronic autoimmune disorder characterized by inflammation of the exocrine glands, leading to dry mouth and dry eyes. This study investigates the role of interleukin-9 (IL-9) and T helper 9 (Th9) cells in the pathogenesis of SjD. We found that serum IL-9 levels were significantly elevated in SjD patients and correlated with clinical laboratory parameters, including autoantibody production. In a mouse model of SjD, IL-9 and Th9-associated cytokines were also elevated, a...

Antiphospholipid syndrome (APS) and systemic sclerosis (SSc) are immune-mediated multisystem autoimmune diseases with distinct clinical phenotypes but overlapping pathogenic themes, including immune dysregulation, chronic inflammation, and endothelial injury. Using peripheral blood transcriptome datasets from the Gene Expression Omnibus (GSE102215: 9 APS/9 controls; GSE231691: 49 SSc/18 controls), we performed differential expression analysis within each cohort (limma; |log2FC|>1, P<0.05) and id...

Vaccination frequently elicits suboptimal immunogenicity in organ transplant recipients, particularly those on long-term immunosuppressive therapy, highlighting the need for improved understanding of immunosuppression mechanisms and optimized vaccination strategies. This study enrolled a cohort of 132 individuals and observed significantly lower antibody levels in kidney transplant recipients (KTRs) compared to non-transplant controls (non-KTRs). Antibody levels were inversely associated with bo...

Multiple sclerosis (MS) therapies primarily rely on lymphocyte depletion or trafficking blockade, carrying risks of systemic immunosuppression; however, such treatments have limited efficacy in secondary progressive multiple sclerosis (SPMS). Thus, drugs that target stage-specific inflammation without broad immunosuppression are an unmet clinical need. In this double-blind, placebo-controlled phase II trial, 30 patients with relapsing MS received weekly oral OCH or placebo for 24 weeks. In the ...

AimsGestational diabetes mellitus (GDM) is the most common pregnancy-related medical complication. GDM is linked to aberrant immune responses in both mothers and offsprings, specifically, the subsequent development of inflammatory diseases. Whereas prior research has focused on specific immune cell subsets, a comprehensive overview of the impacts of GDM on maternal and fetal immune landscape is lacking. Here, we aim to comprehensively decipher how GDM modulates various immune cell populations in...

RIG-I is a cytosolic immune receptor that provides the first line of defense by detecting viral RNA and triggering antiviral responses. Its physiological role in humans remains unclear, as no patients with complete RIG-I deficiency have yet been reported. We identified a critically ill COVID-19 patient with severe RIG-I deficiency caused by heterozygous RIG-I G731R, a novel dominant loss-of-function variant. The G731R mutation in helicase motif VI disrupts the arginine finger, impairing the ATPa...

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but commonly cause immune-related adverse events (irAEs), whether administered as monotherapy or in combination with other oncological agents. We present the first reported case of ICI-induced granulomatous sialadenitis in a male patient in his mid-fifties with BRAF-V600E-mutated papillary thyroid carcinoma who received sequential treatment with BRAF/MEK inhibitors followed by pembrolizumab. The patient experienced acute-onset...

The Endoplasmic Reticulum AminoPeptidase 2 (ERAP2) gene encodes an aminopeptidase involved in antigenic peptide processing for the MHC-I pathway. Genetic variants in the ERAP2 gene are associated with autoimmune conditions and infectious diseases. The linkage between genetic variants in the ERAP2 gene has given rise to the prevailing assumption that a single ERAP2 allotype with invariant amino acid sequence accounts for all immunological functions of ERAP2. Here, we show by analyzing exon-sequen...

BackgroundAn adverse female sex-bias exists across many autoimmune disorders, yet its underlying mechanisms, particularly the role of sex hormones, remains poorly understood. Furthermore, the physiological influence of sex hormones in regulating T cell function remains undefined. We examined for the critical role of estrogen and progesterone, in regulating CD4+ T cell responses, specifically with respect to inflammation and their bone erosion potential in RA. MethodsInflammatory markers, circul...

Epstein-Barr virus (EBV) is strongly implicated as an essential environmental trigger of multiple sclerosis (MS), yet the host genetic mechanisms governing EBV activity and how infection triggers the disease are not known. We developed a pipeline to quantify EBV DNA from whole-genome sequencing data and applied it to population-scale cohorts. Using this pipeline, we performed a cross-ancestry genome-wide association study (GWAS) of EBV DNA positivity in 617,186 individuals and identified 39 inde...

BackgroundPeanut allergies continuously present urging public health challenges. Oral immunotherapy (OIT) is an important treatment option for peanut allergies, but its effectiveness varies, in terms of inducing desensitization (DS) or achieving long-term sustained unresponsiveness (SU). Identifying biomarkers to predict OIT outcomes is thus of great translational interests. MethodsWe thoroughly analyzed data from the POISED trial and our in-house OPIA trial, with a particular focus on the pean...

BackgroundAtopic dermatitis (AD) is a chronic skin disease that typically occurs in early childhood. In this cross-sectional case-control study, our objective was to employ machine learning approaches to identify novel clusters of protective or susceptibility features associated with AD. Methods and FindingsWe utilised an integrated dataset comprising previously established environmental, cytokine, antibody, and gene expression data from AmaXhosa children, both healthy and with AD, living in ei...

TRAF1 is a pro-survival signaling adaptor that contributes to NF-{kappa}B activation downstream of a subset of TNFR superfamily members. TRAF1 is overexpressed in many cancers of mature B cells, including chronic lymphocytic leukemia (CLL). Previous studies have established that TRAF1 S146 is a target of phosphorylation by the kinase PKN1 and that PKN1 is required to prevent cellular inhibitor of apoptosis protein (cIAP)-dependent degradation of TRAF1 in the CD40 signaling complex. The kinase in...

BackgroundEpstein-Barr virus (EBV) establishes latency in most adults and can be reactivated under conditions of co-infection and immune dysregulation. COVID-19 has been associated with EBV reactivation, primarily in hospitalized cohorts, but EBV shedding in the oral cavity and the extent to which these dynamics trigger a systemic anti-EBV antibody response during acute COVID-19 remain poorly understood. MethodsWe conducted a nested cohort study of 69 community-based participants including 56 S...

Why do some individuals develop mild COVID-19 while others progress to severe disease remains a central challenge in SARS-CoV-2 immunology. In this study, we leveraged the BACO Cohort - a unique historical cohort of immunologically naive, hospitalized COVID-19 patients from the first pandemic wave - to investigate early immune determinants of clinical disease trajectories. Integrating bulk RNA-seq, Olink proteomics, and systems serology, we identified two fundamentally distinct immune trajectori...

BackgroundCervical cancer is one of the most common malignant tumors of the female reproductive system. Existing treatments provide limited benefit for patients with advanced, recurrent or metastatic disease, and reliable prognostic markers are lacking. In this study we integrated multi-omic data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. Protein-coding genes meeting the criteria of an adjusted P value < 0.05 and |log2 fold-change| > 5 were screened; ...

Identification of early interventions to reduce/eliminate asthma - the most common chronic disease among children - could significantly reduce burden on the healthcare system. Large-scale asthma Exposome-Wide Association Studies (ExWAS) could identify potential interventions, however integration of diverse data is required to address association confounders. The CHILD Cohort Study has followed 3,454 healthy Canadian children and their families from early pregnancy, collecting exceptionally diver...

BackgroundTuberculosis (TB) and HIV co-infection cause profound immune dysregulation. Understanding how these infections alter immune cell distribution across systemic and tissue compartments is critical for improving therapeutic and vaccine strategies. MethodsFlow cytometry was used to quantify CD4 and CD8 T cells, B cells, and tissue-resident memory (TRM) T and B cells in peripheral blood mononuclear cells (PBMCs), lung tissue, bronchoalveolar lavage (BAL), spleen, and lung-draining hilar lym...