Research

Nat Chem Biol. 2025 Sep 1. doi: 10.1038/s41589-025-02012-0. Online ahead of print.

ABSTRACT

Signal transducer and activator of transcription (STAT) is a family of key transcriptional regulators in immune, epithelial and mesenchymal cells. Aberrant STAT activity is associated with malignancy, autoimmunity and immunodeficiency. The STAT signaling pathways are very attractive drug targets; however, validated tools to monitor real-time activation of STATs are lacking. Here, we developed a class of highly sensitive genetically encoded STAT biosensors, termed STATeLights, which allowed direct and continuous detection of STAT activity in live cells with high spatiotemporal resolution. Using human STAT5A, we demonstrate the versatility of STATeLight5A to quantify the activation of wild-type STAT5 versus disease-associated STAT5 mutants and to precisely select compounds targeting the STAT5 signaling pathway. Moreover, STATeLight5A also facilitated real-time tracking of STAT5 activation in human primary CD4⁺ T cells. Collectively, our biosensors open up unprecedented possibilities of studying STAT biology and druggability in various cellular contexts.

PMID:40890507 | DOI:10.1038/s41589-025-02012-0

Neoreviews. 2025 Sep 1;26(9):e600-e614. doi: 10.1542/neo.26-9-051.

ABSTRACT

Severe combined immunodeficiency (SCID) is a rare and life-threatening disease, characterized by an intrinsic defect of the hematopoietic stem cell that disrupts appropriate T lymphocyte maturation. Previously, early diagnosis of SCID used to require an experienced physician who identified patients with abnormal absolute lymphocyte count and distinct clinical manifestations. Over the past few decades, the implementation of universal newborn screening has enhanced our diagnostic capabilities. The Pediatric Immune Deficiency Treatment Consortium updated the definitions of SCID in 2022, providing a comprehensive approach to differentiate patients with typical SCID from leaky or atypical SCID, and Omenn syndrome from those without SCID. SCID is caused by multiple genetic abnormalities with different phenotypes involving T cells and possibly natural killer cells, and B cells. The management of patients with SCID requires a multifocal approach with early interventions to prevent infections and the concurrent planning of a curative therapy such as hematopoietic stem cell transplantation or, in some cases, gene therapy. Early intervention in affected patients with the absence of infection is a predictor of good long-term outcomes, but because of evolving bone marrow transplant and gene therapy techniques, patients need to be monitored long term to assess for possible late side effects. This review will focus on the most common genetic causes of SCID and their distinct characteristics, acute management, and curative options.

PMID:40887076 | DOI:10.1542/neo.26-9-051

J Biol Chem. 2025 Aug 28:110643. doi: 10.1016/j.jbc.2025.110643. Online ahead of print.

ABSTRACT

ADAM17 is a cell surface protease that controls the release of the ectodomains of signaling proteins including EGFR ligands and the primary inflammatory cytokine TNF. Reflecting this important role in signaling, dysregulated ADAM17 activity is linked to many human diseases including immunodeficiency, inflammatory bowel disease (IBD), rheumatic arthritis, cancer, and Alzheimer’s disease. iRhom2, a pseudoprotease of the rhomboid-like superfamily, has evolved to be a multifunctional regulatory co-factor of ADAM17. Recent structural and functional work has begun to reveal how the iRhom2 transmembrane and extracellular domains act to control ADAM17 activity. The cytoplasmic domain, however, remains less explored. Here, using a combination of proteomic, genetic and biochemical approaches, we report three distinct mechanisms by which the cytoplasmic domain of iRhom2 contributes to ADAM17 regulation. First, upon oncogenic KRAS signaling, the serine/threonine kinase RSK2 is recruited to the iRhom2 cytoplasmic N-terminus, and coordinates with phosphorylated ERK to activate the iRhom2/ADAM17 sheddase complex. Second, we show that iRhom2 may have an inhibitory function on ADAM17 at the cell surface: stabilising iRhom2 at cell surface by overexpressing iRhom2’s cytoplasmic binding partner, FRMD8, inhibits PMA-stimulated ADAM17 activity. Third, we have identified a previously undefined motif (RKR) in the iRhom2 cytoplasmic domain that represses unstimulated ADAM17 activity. Overall, these findings reveal the complex regulatory system by which the iRhom2 cytoplasmic tail transduces cellular signals to regulate ADAM17 activation, potentially paving the way towards understanding and possibly manipulating the iRhom2/ADAM17 complex in health and disease.

PMID:40885391 | DOI:10.1016/j.jbc.2025.110643

Calcif Tissue Int. 2025 Aug 30;116(1):115. doi: 10.1007/s00223-025-01428-z.

ABSTRACT

Severe, treatment-refractory or early-onset osteoporosis should prompt evaluation for secondary causes. Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterised by markedly elevated serum IgE, recurrent infections and skeletal anomalies, including osteoporosis and increased fracture burden. We present two cases of severe osteoporosis in early postmenopausal women. Both women exhibited markedly elevated IgE levels, raising the possibility of underlying HIES. Case 1, despite anabolic and anti-resorptive treatment, experienced multiple fragility fractures, with fracture burden out of keeping with bone mineral density. Case 2 did not respond to bisphosphonate therapy and developed a severe erythematous skin reaction following romosozumab therapy. Both cases highlight the importance of evaluating for secondary causes of osteoporosis. The novel reaction to romosozumab in Case 2 raises questions about its use in patients with immune dysregulation.

PMID:40884553 | DOI:10.1007/s00223-025-01428-z

World J Clin Pediatr. 2025 Sep 9;14(3):107165. doi: 10.5409/wjcp.v14.i3.107165. eCollection 2025 Sep 9.

ABSTRACT

Inflammatory bowel disease (IBD) is a group of chronic disorders that cause relapsing inflammation in the gastrointestinal tract (GIT). It results either from gene-environment interactions or as a monogenic disease resulting from pathogenic mutations causing impairment in the protective mechanism of the GIT. Around 10%-15% of patients with very early onset IBDs may have an underlying monogenic condition. Monogenic IBD is very different from complex forms of polygenic IBD in the underlying molecular basis of uncontrolled intestinal inflammation, age of onset, extraintestinal comorbidities as well as treatment modality. An in-depth understanding of this distinct form of IBD is essential for deciding an appropriate therapeutic approach as well as prognostication. In this review, we aim to discuss about the epidemiology, clinical presentation, diagnostic approach, therapeutic challenges and latest advances in patients with monogenic IBD.

PMID:40881087 | PMC:PMC12305043 | DOI:10.5409/wjcp.v14.i3.107165

PLoS One. 2025 Aug 29;20(8):e0328828. doi: 10.1371/journal.pone.0328828. eCollection 2025.

ABSTRACT

BACKGROUND: Cerebellar atrophy is a known feature of ataxia-telangiectasia (A-T). However, basal ganglia dysfunction contributing to extrapyramidal movement disorders in A-T remains understudied.

OBJECTIVES: To characterize basal ganglia abnormalities in A-T using a normative self-supervised deep autoencoder trained on MRI-based diffusion and perfusion features from healthy children.

METHODS: Mean values of apparent diffusion coefficient and cerebral blood flow perfusion maps were extracted from seven regions-of-interest: caudate, hippocampus, pallidum, putamen, thalamus, cerebellar gray matter and cerebellar white matter. A normative deep autoencoder that reconstructs these features was trained on healthy subjects. Reconstruction errors for healthy and A-T participants were computed. We used Shapley Additive Explanations (SHAP) to identify the most influential features contributing to the features’ reconstruction predictions. Correlations between reconstruction errors and clinical scores in A-T patients were evaluated.

RESULTS: Features were correctly reconstructed in controls but not A-T participants, who showed significantly higher reconstruction errors. Hippocampus, caudate and putamen diffusion, and caudate and putamen perfusion were overestimated, and cerebellar diffusion and pallidum perfusion underestimated, in participants with A-T. SHAP scores revealed that caudate, putamen, and hippocampus perfusion had the greatest influence on the reconstruction of perfusion features. In contrast, cerebellar diffusion and caudate perfusion had the greatest influence on the reconstruction of diffusion features. Exploratory analysis showed that extrapyramidal movement sub-scores from A-T participants correlated with perfusion and diffusion reconstruction errors from cerebellar and subcortical structures.

CONCLUSION: Our findings suggest that pallidum, caudate, and cerebellar gray matter are potential targets for novel treatment approaches for A-T. The approach enables identification of subtle tissue anomalies at an individual level, allowing tailored approaches.

PMID:40880371 | DOI:10.1371/journal.pone.0328828

Sci Adv. 2025 Aug 29;11(35):eadw2464. doi: 10.1126/sciadv.adw2464. Epub 2025 Aug 29.

ABSTRACT

The autosomal dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency, which originates from heterozygous missense mutations in the signal transducer and activator of transcription 3 (STAT3) gene. It is accepted that most STAT3 variants causing AD-HIES are dominant negative. Whether haploinsufficient mutations cause a phenotype in humans is still debated. We report on a family with a heterozygous STAT3 nonsense mutation that led to rapid decay of the mutant mRNA and protein, leading to haploinsufficiency. To explore STAT3 heterozygosity, we created a Stat3 haploinsufficient (Stat3^+/-) mouse model in which we found that Stat3^+/- mice had increased IgE serum levels, reduced T_H17 cell differentiation, and were susceptible to a cutaneous Staphylococcus aureus infection. Together, our findings provide mechanistic evidence for the impact of haploinsufficiency in STAT3 with residual protein expression as an important cause for immune deficiency. The implications extend to the diagnosis of immunodeficiency disorders and to the design of gene therapy in situations where gene dosage matters.

PMID:40880472 | DOI:10.1126/sciadv.adw2464

Eur J Immunol. 2025 Jul;55(7):e70015. doi: 10.1002/eji.70015.

ABSTRACT

STAT3-hyper-IgE syndrome (STAT3-HIES) is an inborn error of immunity caused by heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3). In this study, we evaluate the functional relevance of a previously undescribed heterozygous STAT3 variant in a patient with clinical findings of STAT3-HIES. Flow cytometry, quantitative real-time PCR, pull-down assays, native PAGE, DNA-binding ELISA, and 3D-structural data analysis were performed. Genetic analysis identified the heterozygous STAT3 variant NM_139276.2:c.2127G>C (NP_644805.1:p.(K709N); short: p.K709N) in a patient with a clinical and laboratory phenotype characteristic of STAT3-HIES, including early onset severe eczema, chronic lung disease, eosinophilia, and elevated serum IgE levels. While STAT3 p.K709N did not significantly affect STAT3 phosphorylation, STAT3 target gene expression was impaired in patient cells. Expression of STAT3 p.K709N and wild-type STAT3 in STAT3-deficient cells indicated a dominant-negative effect by the mutation. Analysis of 3D-structural data and modeling suggested a central role of the affected amino acid K709 in stabilizing a C-terminal loop in STAT3 essential for dimer formation. Consequently, p.K709N resulted in diminished STAT3 dimerization and reduced DNA binding in patient cells. Functional analyses verified STAT3 p.K709N to cause STAT3-HIES and suggest that STAT3 p.K709N impairs STAT3 dimer formation.

PMID:40878953 | DOI:10.1002/eji.70015

Clin Immunol. 2025 Aug 26:110592. doi: 10.1016/j.clim.2025.110592. Online ahead of print.

ABSTRACT

We report the case of a young boy with X-linked agammaglobulinemia (XLA) who developed progressive gait instability and postural difficulties. Initial cerebrospinal fluid (CSF) analyses and viral PCR testing were negative; however, a brain biopsy confirmed chronic enteroviral encephalitis. The patient was treated with two compassionate-use cycles of pocapavir, in combination with ongoing high-dose intravenous immunoglobulin (IVIG) therapy. Treatment was well tolerated and led to partial neurological improvement followed by clinical stabilization. This case highlights the diagnostic challenges of enteroviral encephalitis in immunocompromised patients and suggests that investigational antivirals such as pocapavir may offer therapeutic benefit in selected cases.

PMID:40876609 | DOI:10.1016/j.clim.2025.110592

Biomedicines. 2025 Jul 28;13(8):1836. doi: 10.3390/biomedicines13081836.

ABSTRACT

Primary and secondary immunodeficiencies comprise a wide array of illnesses marked by immune system abnormalities, resulting in heightened vulnerability to infections, autoimmunity, and cancers. Notwithstanding progress in diagnostic instruments and an enhanced comprehension of the underlying pathophysiology, delayed diagnosis and underreporting persist as considerable obstacles. The implementation of artificial intelligence into clinical practice has surfaced as a viable method to enhance early detection, risk assessment, and management of immunodeficiencies. Recent advancements illustrate how artificial intelligence-driven models, such as predictive algorithms, electronic phenotyping, and automated flow cytometry analysis, might enable early diagnosis, minimize diagnostic delays, and enhance personalized treatment methods. Furthermore, artificial intelligence-driven immunopeptidomics and phenotypic categorization are enhancing vaccine development and biomarker identification. Successful implementation necessitates overcoming problems associated with data standardization, model validation, and ethical issues. Future advancements will necessitate a multidisciplinary partnership among physicians, data scientists, and governments to effectively use the revolutionary capabilities of artificial intelligence, therefore ushering in an age of precision medicine in immunodeficiencies.

PMID:40868091 | DOI:10.3390/biomedicines13081836