Liam Golding

Samra, Sharma, et al. identify biallelic loss-of-function variants in OSMR as the cause of a new human primary atopic disorder characterized by severe early-onset eczema, eosinophilia, and elevated IgE. Loss of OSMRβ surface expression abolishes OSM-dependent STAT signaling, revealing a key role for OSM-OSMR signaling in maintaining cutaneous immune homeostasis.

Primary atopic disorders (PADs), a subset of inborn errors of immunity, are a growing group of more than 50 monogenic diseases characterized by severe, early-onset allergic inflammation, often coexisting with immune deficiency or dysregulation. Once considered clinical curiosities, PADs have emerged as powerful human models for understanding immune homeostasis. Advances in next-generation sequencing have accelerated gene discovery, revealing that allergic disease can arise from disruption of interconnected regulatory systems rather than immune hyperactivity alone. Here, we synthesize insights from genetically defined PADs to illustrate how defects across epithelial barrier function, immune signaling, cytoskeletal organization, antigen receptor pathways, lymphocyte repertoire, and regulatory networks converge on impaired tolerance and persistent type 2 inflammation. Beyond mechanistic insights, PADs provide a framework for precision therapy enabling targeted use of cytokine inhibitors, JAK inhibitors, biologics, hematopoietic stem cell transplantation, and emerging gene therapies. These insights bridge rare and common disease, informing the pathophysiology and treatment of polygenic atopy.

BackgroundRespiratory syncytial virus (RSV) is the leading cause of respiratory infection in young children. Although passive immunization strategies are available for infants, no immunization options exist for toddlers, and the relationship between population immunity and epidemic intensity remains poorly understood. Measuring maternally derived RSV antibodies in newborns could provide a scalable sentinel approach to monitor population immunity and inform prevention strategies.ObjectivesTo demonstrate the feasibility of using residual newborn dried blood spots (NDBS), collected universally at birth, to quantify population-level RSV antibody immunity.Study designWe developed a method to quantify RSV antibody levels and function using residual NDBS from the British Columbia Newborn Screening Program. Assay performance and stability were first evaluated using adult dried blood spot and serum controls, then applied to two NDBS datasets.ResultsIn adult dried blood spots, IgG against RSV pre-fusion (pre-F) protein was stable for at least 30 days and ⁓20-fold lower than corresponding sera. In NDBS, pre-F IgG levels remained stable for 140 days at room temperature, correlated with viral neutralization titers (ρ=0.64, p<0.0001; N=159), and showed antigen specificity through competitive blocking with soluble post-F protein across multiple RSV antigens (pre-F, post-F, N, Ga, Gb). ⁓42% of samples were below the lower limit of quantification.ConclusionsRSV antibody immunity can be quantified from residual NDBS. This scalable approach enables population-level surveillance of RSV immunity and supports large-scale studies of seasonal RSV dynamics, viral circulation, epidemiology and correlates of protection across regions.

Inborn errors of immunity (IEIs) are caused by deleterious variants in immune-related genes. ASXL1 is an epigenetic modifier not previously linked to an IEI. Clonal hematopoiesis and hematologic neoplasms often feature somatic ASXL1 variants, and Bohring–Opitz syndrome, a neurodevelopmental disorder, is caused by heterozygous truncating ASXL1 variants. We present an IEI caused by biallelic germline missense variants in ASXL1. The patient had a history of hematologic abnormalities and viral-associated complications, including chronic macrocytosis, persistent vaccine-strain rubella granulomas, and EBV-associated Hodgkin lymphoma. Immunophenotyping revealed loss of B cells, hypogammaglobulinemia, and impairments in cytotoxic T and NK cell populations. T cells exhibited skewing toward an exhausted memory phenotype, global DNA methylation loss, and increased epigenetic aging. These aberrations were ameliorated by wild-type ASXL1 transduction, confirming the patient variants’ pathogenicity. This study defines a novel human IEI caused by ASXL1 deficiency, a diagnosis that should be considered in individuals with chronic viral infections, viral-associated malignancies, and combined immune deficiency.

ThPOK is a transcription factor that acts as a master regulator of CD4+ T cell lineage commitment. We report the first human disease caused by a genetic alteration in ThPOK, specifically, a damaging heterozygous de novo variant in ThPOK (NM_001256455.2:c.1080A>C, p.K360N). This patient exhibited the unusual constellation of persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The ThPOKK360N variant displayed abnormal multimorphic activity, interfering with ThPOKWT (antimorph), failing to bind wild-type ThPOK consensus sequences (amorph), and showing novel DNA-binding specificity (neomorph). Single-cell RNA sequencing revealed defects in CD4+ and CD8+ T cell maturation and activation (hypomorph). Recapitulated in lentivirally transduced healthy control T cells and fibroblasts, the transcriptomic analysis showed ThPOKK360N-transduced T cells had impaired TCR activation and ThPOKK360N-transduced fibroblasts with increased profibrotic gene expression. This novel human disease confirms ThPOK’s role in CD4+ T cell development but also uncovers novel roles in TCR activation and regulation of fibrotic pathways in fibroblasts.

Longitudinal measurements of respiratory syncytial virus (RSV) immunity over 4 winter seasons reveal that viral neutralization titers, RSV prefusion F protein (pre-F)–specific immunoglobulin M and immunoglobulin G (IgG) levels, and RSV antibody–dependent cellular phagocytosis function gradually returned to prepandemic levels in female healthcare and school workers of childbearing age after 2 winter seasons, following the resurgence of RSV cases in the Vancouver metropolitan region (British Columbia, Canada). In contrast, pre-F IgG avidity profiles remained unchanged. These findings support the notion that repeated viral infections are necessary to maintain high RSV antibody levels in the population.

ThPOK is best known as a regulator of CD4+ T cell lineage commitment, although it was initially cloned as a suppressor of collagen expression in the skin. The role of ThPOK has not been formally established in humans since individuals with damaging variants in ThPOK have not yet been identified. Here, we report the first case of a human with a damaging heterozygous de novo variant in ThPOK causing a syndrome encompassing CD4+ T cell deficiency, allergy, fibroinflammatory interstitial lung disease, developmental delay, and growth failure. The patient variant, ThPOK K360N, exhibited abnormal multimorphic activity, including interfering with ThPOK WT in regulating gene regulation (antimorph). Protein-DNA interaction assays showed inability of ThPOK K360N to bind to wild-type consensus sequences (amorph) and revealed a novel DNA-binding specificity (neomorph). Single-cell RNA sequencing of peripheral blood revealed potential developmental defects in maturation and activation of CD4+ and CD8+ T cells (hypomorph). To establish causality, we recapitulated the observed cellular defects in lentivirally transduced healthy control T cells and pulmonary fibroblasts. Transcriptomic analysis showed that T cells transduced with ThPOK K360N lacked the upregulation of activation, proliferation, and functional pathways observed in ThPOKWT-transduced cells. When overexpressed in healthy control fibroblasts, ThPOK K360N significantly increased the expression of pro-fibrotic genes implicated in pulmonary fibrosis, indicating a defect in regulating collagen expression. This novel human disease caused by a multimorphic variant in ThPOK confirms its role in CD4+ T cell development in an intact human context, while also revealing an unanticipated role for ThPOK in T cell function and the regulation of fibrotic pathways in fibroblasts.

Objective: Little is known about the interplay between gut microbiome and SARS-CoV-2 vaccine immunogenicity. In this prospective observational study, we investigated associations between the gut microbiome, habitual dietary fibre intake, and mRNA vaccine-elicited immune responses, including anti-Spike IgG, avidity, and ACE-2 competition (surrogate neutralization). Design: 16S rRNA sequencing and short-chain fatty acid analyses were undertaken using stool samples collected from 48 healthy individuals at baseline and twelve-weeks after 1 ^st BNT162b2 SARS-CoV-2 vaccine dose. Associations between gut microbiome data and SARS-CoV-2 spike and RBD IgG levels, competitive binding antibodies, and anti-SARS-CoV-2 spike total relative fractional avidity assays were evaluated. A validated dietary fibre intake food frequency questionnaire was also used to correlate habitual dietary fibre intakes with vaccine responses. Results: Our data revealed several baseline bacterial taxa, including Prevotella, Haemophilus and Veillonella (pBacteroides spp. (pBifidobacterium animalis , (p=0.003), amongst others, were positively associated with antibody avidity. Conversely, concentrations of isovaleric and isobutyric acid were higher in individuals with the lowest SARS-CoV-2 vaccine responses (pst and 2 ^nd dose. How this study might affect research, practice, or policy: Our data suggests that therapeutic interventions which target the gut microbiome, including dietary modification, as well as pre-, pro-, and post-biotics, could enhance BNT162b2 vaccine immunogenicity, thus helping in the fight against COVID-19.