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Sultan Qaboos Univ Med J. 2025 May 2;25(1):689-696. doi: 10.18295/2075-0528.2896. eCollection 2025.

ABSTRACT

OBJECTIVES: Inborn errors of immunity (IEI) are a diverse group of disorders arising from defects in the development and/or function of the immune system. However, data concerning the microbiological aspects of infections and direct causes of mortality in patients with IEI are limited and fragmented. This study aimed to elucidate the causes of disease and terminal events leading to death in a cohort of patients with IEI.

METHODS: This retrospective study included deceased patients who were diagnosed with primary immunodeficiency at Sultan Qaboos University Hospital in Muscat, Oman, over an 18-year period between 2005 and 2023. Data on clinical features, infections, isolated microorganisms and terminal events leading to death were collected and analyzed.

RESULTS: A total of 53 cases were included in this study. The mean age at death was 9.1 ± 10.4 years (median: 3.9 years, interquartile range: 15.2 years, range: 0.2-45.2 years). Prior to death, the most frequently isolated microorganisms included Pseudomonas spp. (41.5%), Pseudomonas aeruginosa (34%), Candida spp. (28.3%), cytomegalovirus (26.4%) and Hemophilus influenzae (20.8%), among others. The predominant terminal events leading to death were septicemia/septic shock (64.2%), pneumonia/adult respiratory distress syndrome/multiorgan dysfunction syndrome (49.1%), disseminated viral disease (22.6%) and bronchiectasis/pulmonary hypertension/haemorrhage (20.8%).

CONCLUSION: Understanding factors contributing to terminal events in IEI patients can inform early intervention strategies and potentially reduce mortality rates.

PMID:40979612 | PMC:PMC12445312 | DOI:10.18295/2075-0528.2896

Cureus. 2025 Aug 18;17(8):e90448. doi: 10.7759/cureus.90448. eCollection 2025 Aug.

ABSTRACT

Activated PI3 kinase delta syndrome (APDS) is a rare, inherited primary immunodeficiency characterized by gain-of-function mutations in the PIK3CD or PIK3R1 genes, resulting in hyperactivation of the PI3Kδ pathway and consequent immune dysregulation. This review provides an in-depth exploration of the genetic and molecular mechanisms underlying APDS, highlighting the complex interplay between immunodeficiency and autoimmunity. Clinical manifestations include recurrent infections, lymphoproliferation, autoimmune cytopenias, and inflammatory complications, which often begin in early childhood. Diagnostic strategies have evolved with the advent of genetic sequencing and immunologic biomarkers, enabling the more accurate identification and classification of APDS subtypes than previously possible. Therapeutic advances, particularly the development of PI3Kδ inhibitors such as leniolisib and duvelisib, have significantly improved patient outcomes by targeting the underlying molecular defects. Additional management approaches include immunoglobulin replacement, immunomodulators, and hematopoietic stem cell transplantation in severe cases. Despite these advances, challenges such as delayed diagnosis, treatment-related complications, and variability in clinical presentation persist. Continued research on targeted therapies, long-term outcomes, and gene-editing technologies is essential to optimize care and enhance the quality of life for individuals with APDS.

PMID:40978950 | PMC:PMC12446750 | DOI:10.7759/cureus.90448

J Allergy Clin Immunol. 2025 Sep 17:S0091-6749(25)00950-9. doi: 10.1016/j.jaci.2025.09.002. Online ahead of print.

ABSTRACT

The use of artificial intelligence (AI) in primary immunodeficiencies (IEI) offers transformative potential in diagnostics and disease management but faces multiple challenges that were discussed at the second Artificial Intelligence in Primary Immune Disease (AIPI) conference, held in New York City (March 19-22, 2025). The conference addressed seven themes: predictive diagnostic algorithms, health equity, industry collaboration, advanced computational tools like large language models (LLMs), patient-led AI initiatives, multi-omics integration, and implementation science. Discussions highlighted the growing impact of AI on diagnostics, genomics, and health systems, emphasizing the need for high-quality, diverse datasets and ethical safeguards to ensure equitable application. Participants stressed that AI alone cannot resolve systemic inequities or delays in diagnosis. Challenges such as the lack of harmonized datasets, the complexity of integrating multi-omics data, ethical concerns, and the difficulty of adapting solutions to low-resource settings were emphasized. Additionally, the use implementation science was point out as one of the major challenges to ensure applicability and scalability in real-world settings. This requires overcoming resistance to adoption, addressing infrastructure gaps, and ensuring regulatory compliance. Collaboration across academia, clinicians, patients, regulators, and industry is essential to ensure AI delivers equitable, lasting benefits for individuals with IEI.

PMID:40972982 | DOI:10.1016/j.jaci.2025.09.002

Mol Pharmacol. 2025 Sep 16;107(10):100071. doi: 10.1016/j.molpha.2025.100071. Online ahead of print.

NO ABSTRACT

PMID:40972475 | DOI:10.1016/j.molpha.2025.100071

3 Biotech. 2025 Oct;15(10):349. doi: 10.1007/s13205-025-04509-w. Epub 2025 Sep 15.

ABSTRACT

EIF5A2, a key member of the EIF family, has not been extensively studied regarding its role and mechanism in pan-cancer. TCGA and GTEx analyses were performed to investigate the differential expression of EIF5A2 in tumors and normal tissues. cBioportal was used to investigate the gene alterations of EIF5A2 in tumors. We used Cox regression and Kaplan-Meier analyses to discuss the impact of EIF5A2 expression on prognosis. Quantitative real-time PCR (qRT-PCR) was used to detect EIF5A2 mRNA levels in 12 cases of fresh liver hepatocellular carcinoma (LIHC) and corresponding adjacent non-tumor tissues. Immunohistochemistry (IHC) was employed to evaluate the expression levels of EIF5A2 in 284 cases of LIHC as well as in adjacent non-tumorous tissues. Furthermore, the study explored the association between EIF5A2 expression and various clinicopathological parameters, along with its prognostic implications. Spearman correlation analysis was used to estimate the relationship between EIF5A2 expression and tumor mutation burden (TMB), microsatellite instability (MSI), and immunologic features. “pRRophetic”R package was utilized to obtain the sensitivity of common drugs. The Gene Set Enrichment Analysis (GSEA) was used to study the functional enrichment analysis of EIF5A2-related genes. EIF5A2 was overexpressed in most tumors using TCGA and GTEx databases. Cox regression analysis demonstrated that high EIF5A2 expression was associated with unfavorable overall survival (OS) and disease-specific survival (DSS) in head and neck squamous cell carcinoma (HNSC), brain lower grade glioma (LGG), and LIHC. The frequency of EIF5A2 gene alterations was the highest in lung squamous cell carcinoma (LUSC). EIF5A2 expression was associated with TMB, MSI, and immune cell infiltration in some tumors. We performed IHC and qRT-PCR to evaluate EIF5A2 expression in HCC and normal tissues, and found upregulation of EIF5A2 expression at the mRNA and protein levels in LIHC. There was a correlation between EIF5A2 expression and tumor size, tumor grade, and TNM stage in LIHC. Kaplan-Meier survival suggested that the overexpression EIF5A2 group had unfavorable outcomes in LIHC. EIF5A2 expression was correlated with immune cell infiltration in LIHC. The high EIF5A2 expression group was more sensitive to cisplatin, crizontinib, gemcitabine, and nilotinib in LIHC. High EIF5A2 expression was associated with several pathways, including cell cycle, proteasome, DNA replication, primary immunodeficiency and oocyte meiosis. EIF5A2 may serve as a potential prognostic marker and a latent focus for cancer immunological treatment.

PMID:40964657 | PMC:PMC12436671 | DOI:10.1007/s13205-025-04509-w

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2025 Sep;41(9):832-836.

ABSTRACT

Severe combined immunodeficiency (SCID) represents a group of genetically heterogeneous disorders characterized by mutations that lead to profound defects in both humoral and cellular immunity. Transplacental maternal engraftment (TME) is a frequently observed complication in SCID. While most cases of SCID with TME exhibit no substantial impact on disease progression, a subset of patients may encounter diagnostic delays or therapeutic challenges due to TME interference. Furthermore, TME may predispose these individuals to graft-versus-host disease (GVHD) prior to hematopoietic stem cell transplantation, thereby increasing diagnostic complexity and treatment risks. This review systematically examines the etiology and clinical manifestations of SCID associated with TME, analyzes its implications for disease management, and evaluates current detection methodologies. The synthesized evidence provides a theoretical foundation for future research and offers potential insights into the clinical diagnosis and management of SCID associated with TME.

PMID:40962442

Cell Rep Med. 2025 Sep 16;6(9):102355. doi: 10.1016/j.xcrm.2025.102355.

ABSTRACT

Ataxia-telangiectasia (A-T) is a hereditary neurodegenerative disorder caused by mutations in the ATM (ataxia-telangiectasia mutated) gene. Although existing rodent models reproduce some of the multi-systemic features of A-T, they notably fail to recapitulate the severe neurological manifestations, particularly the profound cerebellar atrophy and associated ataxia. To address this limitation, we have generated ATM-deficient rhesus macaques using CRISPR-Cas9. These macaques exhibit hallmark features of A-T, including growth retardation, lymphopenia, elevated a-fetoprotein levels, oculocutaneous telangiectasias, heightened sensitivity to ionizing radiation, and most critically, cerebellar atrophy, Purkinje cell loss, and early-stage cerebellar neurodegeneration leading to significant motor impairments. Single-nucleus transcriptomic profiling of the cerebellum revealed pronounced gene expression changes associated with ATM deficiency, particularly in molecular layer interneurons (MLIs), which are implicated in Purkinje cell loss. This non-human primate model provides deeper insights into the pathogenesis of A-T and represents a promising and valuable platform for developing therapeutic strategies.

PMID:40961921 | DOI:10.1016/j.xcrm.2025.102355

J Hum Immun. 2025 Nov 3;1(4):e20250016. doi: 10.70962/jhi.20250016. Epub 2025 Aug 19.

ABSTRACT

Predominantly antibody deficiency (PAD) is the most prevalent form of human inborn errors of immunity (IEI). PAD is characterized by recurrent bacterial infections, immune dysregulation, and impaired immunoglobulin production. A monogenic cause of PAD can be identified in about 20% of cases. Approximately 10% of patients carry heterozygous mutations in the tumor necrosis factor receptor superfamily member 13B gene (TNFRSF13B), encoding the B cell surface protein TACI. Heterozygous variants in TNFRSF13B are not sufficient to cause PAD, as approximately 1% of the healthy population carries one of these variants. To identify additional genetic contributors to the immune defect in these individuals, we examined the exomes of 161 PAD patients with rare-damaging variants in TNFRSF13B. We identified (i) biallelic mutations in TNFRSF13B, (ii) the HLA-class II marker (DPA1*03), and (iii) multiple single nucleotide polymorphisms in known B-cell related genes, as additional genetic risk factors. Moreover, pathogenic mutations in other known IEI genes were presented in 16% of patients with heterozygous TNFRSF13B variants.

PMID:40959164 | PMC:PMC12435966 | DOI:10.70962/jhi.20250016

Allergy Asthma Proc. 2025 Sep 1;46(5):398-405. doi: 10.2500/aap.2025.46.250048.

ABSTRACT

Background: Hereditary angioedema (HAE) substantially impairs patients’ quality of life (QoL), both physically and psychologically, with unpredictable attacks that cause disruptions in education, work, and social life. Objective: To identify key themes and existing knowledge gaps around the multifaceted burden of HAE. Methods: A literature review was conducted in January 2024 through a search of medical literature data bases. English-language studies considered relevant to patient burden and QoL were selected for analysis. Results: A total of 48 studies were included in the analysis; 50% were cross-sectional and 54% were conducted in North America. Twenty-three studies reported outcomes on QoL and pain, 10 studies reported outcomes on psychological distress, 16 studies reported outcomes on experiences with long-term prophylaxis, 36 studies reported outcomes on HAE attacks, and one study detailed caregiver burden. Patients with HAE had worse QoL compared with the general population, and worse QoL was associated with a higher frequency or severity of attacks, anxiety, and depression. The use of long-term prophylaxis improved QoL, and treatment satisfaction was driven by improvements in mental health and fostering a sense of control and independence. Conclusion: HAE continues to substantially impact QoL of patients. Although recent work has demonstrated progress in standardizing assessment tools for QoL in HAE, additional research is needed to determine the correlation between individual patient factors and QoL.

PMID:40958183 | DOI:10.2500/aap.2025.46.250048

Allergy Asthma Proc. 2025 Sep 1;46(5):354-361. doi: 10.2500/aap.2025.46.250049.

ABSTRACT

Background: In 1970, W.B. Schwartz predicted that computers would revolutionize medicine by enhancing the physician’s intellect, a vision that has largely materialized in the past 5 decades. Recent advancements in artificial intelligence (AI), especially in health care, have transformed AI from a conceptual tool into a fundamental part of clinical practice. AI has been successfully applied in diagnostic imaging, health system management, and patient care workflows. Within immunology, AI’s potential for diagnosing and managing complex conditions such as inborn errors of immunity (IEI) is increasingly recognized. This article explores the evolving role of AI in the diagnosis and treatment of IEIs, highlighting its potential to advance precision medicine in allergy/immunology. To illustrate this potential, six representative IEIs were selected, each accompanied by a clinical vignette that summarizes the patient history and laboratory findings. These include severe combined immunodeficiency, common variable immunodeficiency, chronic granulomatous disease, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and the activated PI3K delta syndrome. Methods: An extensive literature review was conducted in medical literature data bases by applying terms such as primary immune deficiency, inborn errors of immunity (IEIs), and allergy. The search focused on identifying studies that explored the intersection of AI technologies with immunology, particularly with regard to the diagnosis and management of IEIs. Results: The literature review identified a growing body of work on the application of AI in allergy and immunology, with 1907 articles on AI and allergy, 16 of which focused specifically on IEI. AI has shown promise in diagnostic accuracy, particularly in rare and complex immunologic conditions, and in improving the efficiency of clinical decision-making. Conclusion: AI holds significant potential for the allergist/immunologist by revolutionizing the diagnosis and treatment of IEIs. By enhancing diagnostic precision, improving patient care workflows, and enabling personalized treatment strategies, AI can advance the practice of immunology. However, challenges such as data quality, model generalizability, and ethical considerations must be addressed to fully harness AI’s capabilities in the clinical setting. This article highlights the transformative potential of AI in immunology and proposes its integration into clinical practice for better patient outcomes.

PMID:40958180 | DOI:10.2500/aap.2025.46.250049