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Front Immunol. 2025 Nov 28;16:1717692. doi: 10.3389/fimmu.2025.1717692. eCollection 2025.

ABSTRACT

BACKGROUND: Gain-of-function (GOF) mutations in STAT1 cause a combined immunodeficiency characterized by chronic mucocutaneous candidiasis (CMC), recurrent infections, and autoimmunity. Mutations in the DNA-binding domain (DBD) have previously been associated with poor outcomes, but the contributions of specific variants to clinical phenotype remain unexplored.

METHODS: We performed a systematic literature review to identify patients with confirmed STAT1 GOF mutations, integrating new cases with a previously reported international cohort. Clinical and genetic data were analyzed at both domain and mutation level to define genotype-phenotype correlations.

RESULTS: A total of 533 unique patients from 36 countries were identified, harboring 135 distinct mutations. As previously reported, DBD mutations were associated with increased risk of systemic infections, bronchiectasis, autoimmunity, and reduced survival. However, mutation-level stratification revealed that the T385M variant accounted for much of this effect. Compared with both other DBD mutations and mutations elsewhere in STAT1, T385M conferred significantly higher rates of infection, bronchiectasis, autoimmunity, and premature death (p < 0.001). Conversely, certain coiled-coil (CC) domain mutations, such as R274Q, were associated with milder disease and improved survival.

CONCLUSION: Our findings demonstrate that the adverse prognosis previously ascribed to DBD mutations in STAT1 GOF is predominantly driven by the T385M variant. Mutation-specific, rather than domain-level, stratification is therefore essential for accurate risk assessment and clinical management. In particular, patients predicted to have severe disease, such as those with the T385M mutation should be considered early for curative interventional therapies such as stem cell transplant or gene therapy.

PMID:41394881 | PMC:PMC12698592 | DOI:10.3389/fimmu.2025.1717692

Front Immunol. 2025 Nov 28;16:1725282. doi: 10.3389/fimmu.2025.1725282. eCollection 2025.

ABSTRACT

OBJECTIVE: In this study, we analyzed a large cohort of Algerian patients with inborn errors of immunity (IEI) to delineate the burden, spectrum, and distribution of autoimmune and autoinflammatory manifestations.

METHODS: This retrospective cohort study was based on recorded data from 825 Algerian patients with IEI. For each patient, autoimmune and autoinflammatory complications occurring before and/or after IEI diagnosis were systematically assessed and documented.

RESULTS: Autoimmune and/or autoinflammatory manifestations were observed in 217 patients (26.3%) and, notably, represented the initial clinical presentation in nearly half. Autoimmune features were documented in 163 patients (19.8%), including 26 (3.2%) with concurrent autoinflammatory findings, whereas isolated autoinflammatory conditions were observed in 54 patients (6.5%). A broad spectrum was observed, with autoimmune cytopenias predominating (11.4%), followed by gastrointestinal (7.8%), rheumatologic (5.3%), and endocrine (3.4%) disorders. Immune dysregulation was a recurrent theme across all IEI categories, with a distinct, disease-specific, clustering of autoimmunity and autoinflammation. Autoimmune cytopenias predominated in T-cell defects, including hypomorphic RAG and CD3γ deficiencies; Inflammatory bowel disease (IBD) was enriched in ARPC1B, DOCK8, and CD55 deficiencies, as well as in chronic granulomatous disease (CGD); endocrine autoimmunity, while a cardinal feature of APECED and IPEX, also characterized STAT1 gain-of-function; inflammatory granulomatous lung disease was a consistent feature in LRBA deficiency; and granulomatous inflammation, whether confined to the lungs or extending to other organs, was prominent in common variable immunodeficiency.

CONCLUSION: Recognition of clustering patterns, particularly autoimmune cytopenias, IBD, and endocrine autoimmunity, has direct clinical implications. These manifestations should be regarded as red flags, guiding targeted evaluation and genetic testing. Mapping such associations not only refines our understanding of pathogenesis but also provides a practical framework for earlier diagnosis and tailored management.

PMID:41394846 | PMC:PMC12698554 | DOI:10.3389/fimmu.2025.1725282

Front Immunol. 2025 Nov 27;16:1741502. doi: 10.3389/fimmu.2025.1741502. eCollection 2025.

NO ABSTRACT

PMID:41394798 | PMC:PMC12696153 | DOI:10.3389/fimmu.2025.1741502

J Clin Immunol. 2025 Dec 12. doi: 10.1007/s10875-025-01970-3. Online ahead of print.

ABSTRACT

INTRODUCTION: Primary ‘predominantly antibody deficiencies’ (PADs) are rare disorders characterized by increased susceptibility to infections, autoimmunity, allergies, and malignancies. Their low prevalence and heterogeneity often delay diagnosis, increasing morbidity and mortality. This study identifies infection patterns in PAD patients and analyzes predictors of bronchiectasis presence at PAD diagnosis (BPAD), aiming to facilitate early diagnosis and improve prognosis.

METHODS: Using fully monitored data on PAD patients without identified genetic origin from the ESID Registry, infection types and pathogens across PADs were compared (chi-square analysis) and predictive factors for BPAD were identified (generalized mixed-effects logistic regression). Additionally, five machine learning classifiers (logistic regression, (bagged) decision tree, random forest and support vector machines) were trained and evaluated by area under the receiver operating characteristics curve (ROC-AUC), confusion matrices and F1-score.

RESULTS: Recurrent respiratory infections were predominant in our cohort of 861 patients from 11 centers. Cultures were conducted in only 5.9-12.3% of infections. Encapsulated bacteria were most frequently isolated. The number of organ systems affected by recurrent infections, occurrence of specific serious bacterial infections, number of identified encapsulated bacteria and common variable immunodeficiency disorders (CVID) diagnosis were predictive of BPAD. Machine learning models achieved moderate discrimination (ROC-AUC range 0.679-0.746).

DISCUSSION: This study highlights the predominance of recurrent and encapsulated bacterial respiratory tract infections in PAD and the underutilization of microbiological cultures. Generalized mixed-effects logistic regression best predicted BPAD. Clinicians should consider immunologic evaluation in patients presenting with serious bacterial infections, multi-system recurrent infections or the repeated isolation of encapsulated bacteria in unusually severe or recurrent infections.

PMID:41384995 | DOI:10.1007/s10875-025-01970-3

EJHaem. 2025 Dec 10;6(6):e70198. doi: 10.1002/jha2.70198. eCollection 2025 Dec.

ABSTRACT

BACKGROUND: Severe congenital neutropenia (SCN) is commonly treated with granulocyte colony-stimulating factor (G-CSF) to reduce neutropenia and the associated risk of infections. Pegfilgrastim, a long-acting form of G-CSF, provides the benefit of less frequent dosing; however, its application in SCN has not been extensively studied. This study aims to assess the long-term safety and effectiveness of transitioning SCN patients from standard G-CSF therapy to pegfilgrastim.

METHODS: We followed eight patients with severe congenital neutropenia (five males, average age 17.8 years) who had been on G-CSF treatment for at least five years. They were switched to pegfilgrastim injections (3-6 mg every 7-14 days). Dosing was individualized to obtain an absolute neutrophil count (ANC) above 1000/µL in all patients. Over a five-year follow-up under treatment with pegfilgrastim, patients were evaluated for ANC levels, infection frequency, adverse effects, and quality of life using the Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) questionnaire. In addition, yearly abdominal ultrasounds, bone density every two years, and genetic screening for RUNX1 and the G-CSF receptor mutations were performed.

RESULTS: Pegfilgrastim significantly improved ANC levels compared to prior G-CSF treatment (p = 0.008). Quality of life (QoL) significantly improved in six patients (p = 0.016). Varying maintenance dosages were required based on the therapeutic response. Bone pain was common, leading to discontinuation in one patient. Two patients developed hip osteopenia, and one showed progressive splenomegaly. Hospitalization rates and infection frequency remained unchanged. Oral ulcers were decreased overall.

CONCLUSION: Pegfilgrastim can be used as an alternative to daily G-CSF in SCN, providing stable ANC and QoL improvements with individualized dosing. Larger studies are warranted to evaluate its long-term safety and efficacy.

CLINICAL TRIAL REGISTRATION: This trial is registered at https://irct.behdasht.gov.ir/ in Iranian Registry of Clinical Trials (IRCT) # IRCT20150125020786N3.

PMID:41384228 | PMC:PMC12690975 | DOI:10.1002/jha2.70198

J Allergy Clin Immunol Pract. 2025 Dec 9:S2213-2198(25)01158-4. doi: 10.1016/j.jaip.2025.12.002. Online ahead of print.

ABSTRACT

Acute rhinosinusitis is common in patients with hypogammaglobulinemia, and occurred with a higher incidence rate in patients with CVID compared to secondary immunodeficiency from B-cell targeted therapy or CAR T-cell therapy. Monitoring and multidisciplinary collaboration are essential for these complex patients.

PMID:41380840 | DOI:10.1016/j.jaip.2025.12.002

Blood Adv. 2025 Dec 11:bloodadvances.2025017243. doi: 10.1182/bloodadvances.2025017243. Online ahead of print.

ABSTRACT

The transcription factor IKAROS plays an important role in lymphocyte development, differentiation, and as a tumor suppressor. To date, more than 70 IKAROS germline heterozygous variants have been reported in patients with primary immunodeficiency (PID)/inborn errors of immunity (IEI) and leukemia, and this number continues to grow. Germline IKAROS loss- and gain-of-function mutations have been linked to immunodeficiency, immune dysregulation, and hematologic malignancies, with a broad spectrum of clinical manifestations. Routine next-generation-sequencing approaches in patients with PID/IEI have facilitated the identification of IKAROS variants, including several cases with variants of uncertain significance (VUS). To determine the VUS’ functional behavior, we systematically generated constructs recapitulating those changes and tested IKAROS functions in vitro. We also conducted an in-depth examination of the C-terminal dimerization domain using alanine-scanning mutagenesis to identify amino acids critical for dimerization and other functions. This work provides a comprehensive description of the biologic impact of 81 previously unreported and/or untested IKAROS variants, including 33 patient-detected germline VUS and 48 laboratory-generated mutations in the dimerization domain. Among them, 15 of the patient-detected variants, primarily mapping to IKAROS DNA-binding or dimerization domains, and at least 21 of the laboratory-generated mutations, impaired IKAROS function and could explain or result in human disease. VUS located in between IKAROS DNA binding and dimerization domains were less likely to be functionally deleterious. Of note, both positive and negative functional data herein generated can be relevant for patients carrying these IKAROS variants, helping to establish a diagnosis and guide treatment decisions.

PMID:41380100 | DOI:10.1182/bloodadvances.2025017243

Cell Mol Immunol. 2025 Dec 10. doi: 10.1038/s41423-025-01373-9. Online ahead of print.

ABSTRACT

T-cell-based therapies have shown remarkable success in combatting hematologic malignancies; however, their efficacy in solid tumors is hindered by the immunosuppressive microenvironment and restricted antigen availability. The use of chimeric costimulatory receptors (CCRs) has emerged as a strategy to improve T-cell function. However, most designs target antigens distinct from the primary antigen receptor, complicating their application across heterogeneous tumors. Here, we characterized the molecular requirements for a platform enabling costimulation in engineered T cells on the basis of dual targeting of a single antigen via a TCR and a CCR. We applied this strategy to the stress ligand BTN3A, which is broadly expressed in solid tumors and is a part of the antigen complex recognized by the γ9δ2TCR. Through structural modeling, alanine scanning, and antibody screening, we determined that 103-4-1BB, a BTN3A-specific CCR, bound to an epitope on BTN3A that was distinct from the γ9δ2TCR epitope. This epitope separation is critical for enabling synergistic coengagement of a single antigen, and the resulting increase in T-cell activation requires both γ9δ2TCR signaling and the trans-acting functionality of the anti-BTN3A-CCR. Moreover, the extracellular domain of 103-4-1BB stabilized T-cell-tumor cell interactions and increased γ9δ2TCR sensitivity, whereas its intracellular 4-1BB signaling domain drove robust proliferation, improved T-cell fitness, and mediated potent tumor control in vivo. Notably, cis-binding of the CCR to BTN3A on engineered T cells promoted survival in the absence of tumor cells, while transbinding to tumor-expressed BTN3A was required for infiltration, tumor clearance, and memory formation. These findings establish a modular framework for designing cis/trans-active CCRs that enhance T-cell function through single-antigen dual engagement, enabling broadly applicable strategies to improve solid tumor immunotherapy.

PMID:41372553 | DOI:10.1038/s41423-025-01373-9

Cells. 2025 Dec 1;14(23):1902. doi: 10.3390/cells14231902.

ABSTRACT

Inborn errors of immunity (IEIs), formerly referred to as primary immunodeficiencies (PID), represent a heterogeneous group of hereditary disorders that significantly increase patients’ susceptibility to severe and recurrent infections. Toll-like receptors (TLRs) play a pivotal role in host defense as fundamental components of innate immunity, while also linking it to adaptive immune responses. This review summarizes advances in understanding the involvement of TLRs in the pathogenesis of IEIs in children. It highlights genetic defects such as deficiencies in MyD88, IRAK-4, NEMO, and TLR3, which lead to distinct clinical phenotypes, for example, increased susceptibility to bacterial infections or herpes simplex virus type-1 (HSV-1) encephalitis. The review also examines more complex disorders, including chronic granulomatous disease (CGD), common variable immunodeficiency (CVID), and X-linked agammaglobulinemia (XLA), in which TLR signaling may be either impaired or dysregulated. This analysis demonstrates the growing importance of functional assays evaluating TLR activity as a diagnostic tool complementary to genetic testing, as well as their potential to precisely characterize immunological phenotypes. Furthermore, current therapeutic perspectives are discussed, including the use of TLR agonists, which have shown promising results in oncology, the role of gene therapy as a causal treatment option, and a proposed diagnostic algorithm incorporating TLR-based evaluation. Despite significant progress, substantial knowledge gaps remain, particularly regarding the full spectrum of TLR signaling abnormalities across IEI subtypes. The conclusions emphasize the need for large-scale, international studies to achieve a comprehensive understanding of pathogenic mechanisms and to develop more targeted and effective therapeutic interventions for children affected by these rare disorders.

PMID:41369391 | DOI:10.3390/cells14231902

Transl Pediatr. 2025 Nov 30;14(11):3204-3212. doi: 10.21037/tp-2025-379. Epub 2025 Nov 25.

ABSTRACT

BACKGROUND: Autosomal dominant signal transducer and activator of transcription 3 (STAT3) mutations are broadly classified into loss-of-function (LOF) and gain-of-function (GOF) variants. LOF mutations in STAT3 are responsible for autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES), a rare primary immunodeficiency disorder. This condition is characterized by elevated serum immunoglobulin E (IgE) levels, chronic eczema, and recurrent respiratory tract infections. Current conventional management strategies include antimicrobial therapy, immunoglobulin replacement, and systematic airway clearance. However, there remains a lack of targeted therapies specifically for AD-HIES, leading to substantial morbidity and significantly compromised quality of life for affected patients. Omalizumab, a monoclonal anti-human IgE antibody, is approved for the treatment of asthma and chronic spontaneous urticaria, but is rarely used in AD-HIES. Relevant studies on the application of omalizumab in AD-HIES patients primarily focus on alleviating skin issues, with significant improvements reported in most cases, but rarely focus on alleviating the lung symptom. We report two cases in which both skin and lung symptoms improved through a combination of omalizumab and conventional treatment.

CASE DESCRIPTION: We report two cases of AD-HIES caused by STAT3 mutations, both complicated by pulmonary involvement. These two patients continued to experience frequent acute infections despite long-term antibiotic use, regular airway clearance, and other conventional treatments. We introduced omalizumab as an adjunct to their existing therapy. After 9 months of treatment, both their skin and lung symptoms were well controlled. The administration of omalizumab in combination with conventional therapy resulted in varying degrees of clinical improvement.

CONCLUSIONS: The combination of omalizumab with conventional therapy may contribute to improved pulmonary and dermatological symptoms in patients with AD-HIES resulting from STAT3 LOF mutations.

PMID:41367532 | PMC:PMC12683399 | DOI:10.21037/tp-2025-379