Pariya Yousefi

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.

Interferon regulatory factors (IRFs) are a family of transcription factors essential for immune system development and host defense. Beyond immunity, IRF6 plays an indispensable role in craniofacial development. Inborn errors of IRFs (IE-IRFs) are a group of rare monogenic disorders caused by damaging variants in the IRF family of genes. In this review, we comprehensively discuss known IE-IRFs and how they contribute to our understanding of human biology, and provide a framework for their diagnosis and treatment. The IRF transcription factors mediate a wide range of biological functions. Accordingly, genetic defects in individual IRFs give rise to diverse human phenotypes, including increased susceptibility to infection, impaired immune development, and even congenital anatomical anomalies. Our collective understanding of IE-IRFs is a powerful example of how integration of clinical care with mechanistic translational research can transform the lives of patients while simultaneously advancing our fundamental understanding of human biology.

Human OTULIN haploinsufficiency predisposes to life-threatening necrosis of the skin and lungs. Disease is triggered by infectious agents, typically Staphylococcus aureus, as well as unknown etiologies. We describe and characterize six unrelated patients who carry rare, predicted deleterious variants of OTULIN in heterozygosity. In addition to staphylococcal infections, the disease in the patients is elicited by previously underappreciated triggers, including mechanical or iatrogenic traumas and pseudomonal or clostridial infections. Severe necrosis of the lungs and/or skin are clinical hallmarks of their disease. By combining in vitro allele characterizations and functional studies in patients’ cells, we demonstrate that the patients suffer from OTULIN haploinsufficiency. We provide guidance for assessing heterozygous OTULIN variants in diagnostic settings by evaluating in silico measures of predicted deleteriousness. The clinical course of the patients expands the genotypic and phenotypic spectrum of OTULIN haploinsufficiency and provides, in the light of a broadening of triggers, leads for therapeutic interventions.

OSMRβ (Oncostatin M receptor beta), a member of the IL-6 superfamily of cell surface receptors, binds OSM and IL-31 and plays a critical role in human immunity. We identified probands from four kindreds with biallelic damaging variants in OSMR , which encodes OSMRβ. Patients had a unifying phenotype for severe widespread, early-onset atopic dermatitis, peripheral eosinophilia, and elevated serum IgE. Patient OSMRβ variants were not appropriately expressed on the cell surface compared to OSMRβ ^WT . Patient OSMR variants showed significantly reduced OSM-mediated activation of STAT1, STAT3, and STAT5 and distinct transcriptional changes in primary dermal fibroblasts, including loss of interferon and inflammatory signatures. These defects were rescued upon lentiviral transduction of WT- OSMR . Together, these data establish that human germline biallelic loss-of-function OSMR variants cause severe allergic disease. We anticipate that this discovery will facilitate the recognition of additional affected individuals and the full definition of this novel primary atopic disorder.

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.

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.