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Front Immunol. 2025 Aug 20;16:1641122. doi: 10.3389/fimmu.2025.1641122. eCollection 2025.

ABSTRACT

WHIM syndrome is typically caused by C-terminal gain-of-function variants in CXCR4, yet clinical heterogeneity suggests additional genetic modifiers. We investigated a family in which the 22-year-old proband harbored two heterozygous variants: a novel CXCR4 missense variant, c.1022C>A (p.S341Y), and a frameshift variant in NFKB1, c.980dup (p.A328Sfs*12). Functionally, CXCR4 p.S341Y substitution – located two residues upstream of the known pathogenic p.E343K variant – increased CXCL12-induced chemotaxis and ERK/AKT signaling while minimally affecting receptor internalization, supporting a partial CXCR4 gain-of-function. The CXCR4 variant co-segregated with mild neutropenia, recurrent respiratory infections, and cutaneous warts in the paternal lineage. In contrast, the maternal NFKB1 variant was associated with agammaglobulinemia and autoimmunity. Their co-inheritance in the proband resulted in a blended WHIM/CVID phenotype characterized by myelokathexis, B-cell maturation arrest and T-cell dysregulation. This case expands the phenotypic spectrum of CXCR4 variants and highlights how multilocus inheritance can obscure classical diagnostic boundaries and guide individualized therapy.

PMID:40909287 | PMC:PMC12405443 | DOI:10.3389/fimmu.2025.1641122

Pediatr Dermatol. 2025 Sep 4. doi: 10.1111/pde.70025. Online ahead of print.

ABSTRACT

A 14-year-old boy was initially diagnosed with erosive oral lichen planus based on clinical and histopathological findings. However, the atypical clinical course and resistance to immunosuppressive therapy raised suspicion for an autoinflammatory disorder or inborn error of immunity. Genetic testing revealed a pathogenic SH2D1A mutation, confirming X-linked lymphoproliferative disease type 1 (XLP-1) in the absence of Epstein-Barr virus exposure. This case highlights oral mucosal lesions as a potential early, EBV-independent manifestation of XLP-1 and emphasizes the importance of considering monogenic immune disorders in persistent, treatment-refractory mucosal disease.

PMID:40907997 | DOI:10.1111/pde.70025

Clin Immunol. 2025 Sep 2:110595. doi: 10.1016/j.clim.2025.110595. Online ahead of print.

ABSTRACT

Primary immunodeficiency diseases (PIDs) are a heterogeneous group of inherited disorders characterized by impaired immune function, leading to increased susceptibility to infections, autoimmunity, and malignancies. While traditionally defined by immune cell defects, emerging evidence highlights the critical role of inflammation in PID pathogenesis. This review explores the intricate relationship between mitochondrial dysfunction and inflammation in PIDs. We examine how genetic defects in PIDs disrupt immune homeostasis, promoting pro-inflammatory states through cytokine dysregulation. Additionally, we discuss the vicious cycle involving oxidative stress, mitochondrial dysfunction, and inflammation, emphasizing the contribution of mitochondrial ROS production, mtDNA damage, and inflammasome activation in sustaining chronic inflammation. Furthermore, we propose that impaired mitochondrial function -potentially through mechanisms involving calcium signalling, ATP synthase regulation, and mitochondrial permeability transition pore formation – may serve as a central link between immune deficiency and hyperinflammation in PIDs. Understanding these complex interactions may provide new insights into the pathogenesis of PIDs and open avenues for targeted therapeutic strategies to improve patient outcomes.

PMID:40907843 | DOI:10.1016/j.clim.2025.110595

Vaccine. 2025 Sep 3;64:127679. doi: 10.1016/j.vaccine.2025.127679. Online ahead of print.

ABSTRACT

Tuberculosis (TB) remains a global health challenge, with around 10 million new cases reported annually and multidrug-resistant strains complicating control efforts. Although incidence has declined in many high-income regions, neonatal populations remain vulnerable, underscoring the continued role of Bacillus Calmette-Guérin (BCG) vaccination. BCG vaccination provides strong protection against severe forms of TB in infancy, though its efficacy against pulmonary disease in adolescents and adults is modest. However, the BCG vaccine carries a risk of disseminated infection in immunocompromised newborns, emphasizing the importance of integrating immunodeficiency screening into vaccination strategies. Slovenia introduced universal newborn screening for inborn errors of immunity (IEI) in 2024 and, in 2025, revised its neonatal BCG vaccination protocol to incorporate screening results before vaccination. Under this approach, blood sampling occurs at ≥48 h, results are available by days 5-7, and BCG is administered between 7 and 14 days of life. This model balances timely TB protection with safety for at-risk infants. The Slovenian experience exemplifies a precision vaccination strategy that integrates real-time immunogenetic data with targeted BCG administration. This approach aligns with World Health Organization goals to modernize TB prevention while awaiting next-generation vaccines and may serve as a guide for other low-incidence countries.

PMID:40907067 | DOI:10.1016/j.vaccine.2025.127679

Transl Psychiatry. 2025 Sep 3;15(1):339. doi: 10.1038/s41398-025-03573-3.

ABSTRACT

This research aimed to develop a machine learning algorithm to predict suicide risk in bipolar disorder (BD) patients using RNA sequencing analysis of lymphoblastoid cell lines (LCLs). By identifying differentially expressed genes (DEGs) between high and low risk patients and their enrichment in relevant pathways, we gained insights into the molecular mechanisms underlying suicide risk. LCL gene expression analysis revealed pathway enrichment related to primary immunodeficiency, ion channels, and cardiovascular defects. Notably, genes such as LCK, KCNN2, and GRIA1 emerged as pivotal, suggesting their potential roles as biomarkers. Machine learning algorithms trained on a subset of the patients and tested on others demonstrated high accuracy in distinguishing low and high risk of suicide in BD patients. Additionally, the study explored the genetic overlap between suicide-related genes and several psychiatric disorders. Our study enhances the understanding of the complex interplay between genetics and suicidal behaviour, providing a foundation for prevention strategies.

PMID:40903457 | DOI:10.1038/s41398-025-03573-3

J Allergy Clin Immunol. 2025 Sep 1:S0091-6749(25)00897-8. doi: 10.1016/j.jaci.2025.08.015. Online ahead of print.

ABSTRACT

BACKGROUND: A scoping review was conducted for the European Society for Immunodeficiencies (ESID) Clinical Working Party (CWP) to evaluate clinical management guidelines for Inborn Errors of Immunity (IEIs). The goal was to identify gaps to inform future guideline development, thereby supporting improved clinical practice and patient outcomes.

METHODS: A search strategy was developed in collaboration with the ESID CWP and an information specialist. The search was performed using Embase, Medline and Google Scholar. Search terms were based on the 2022 International Union of Immunological Societies (IUIS) IEI classification criteria, incorporating Emtree and MeSH terms with Boolean and proximity operators. Titles and abstracts were screened by two independent reviewers using predefined eligibility criteria.

RESULTS: 183 publications underwent full-text screening. Most guidelines focused on treatment of IEIs, followed by diagnosis and prevention. The majority of guidelines (69.9%) were published within the last 5 years. Countries of a high sociodemographic index were involved in the development of the vast majority (98%) of guidelines. Patient involvement and multi-disciplinary team involvement was noted in the development of 6.5% and 5.4% of identified guidelines, respectively. The majority of guidelines (85.2%) were funded by public sources, received no funding or did not report funding. 11.8% and 15% of specific IEI guidelines addressed the management of primary antibody deficiency (PAD) and combined immunodeficiency (CID) with syndromic features, respectively. Importantly, no international consensus guidelines were found for several high prevalence IEIs.

CONCLUSION: This review provides a comprehensive overview of peer-reviewed guidelines for the management of IEIs.

PMID:40902944 | DOI:10.1016/j.jaci.2025.08.015

Cureus. 2025 Aug 2;17(8):e89247. doi: 10.7759/cureus.89247. eCollection 2025 Aug.

ABSTRACT

Hyper IgE syndrome (HIES) is a rare primary immunodeficiency that is characterized by elevated serum IgE levels, recurrent sinopulmonary infections, and chronic eczema, among other symptoms. Though reports on patients with HIES exist, they primarily focus on the clinical features, diagnosis, and management of HIES without detailing surgical interventions. Here, we present the surgical management of an extensive cellulitic infection that developed into skin necrosis in an HIES patient with a history of polysubstance abuse. The patient had a diagnosis of Job’s syndrome, the autosomal dominant form of HIES. In this case, severe infection resulting from immunodeficiency led to cellulitis and full-thickness tissue loss in the left upper limb. Due to the extent of infection and necrosis, multiple debridements and upper extremity reconstructions were necessary for limb preservation. The 625 cm² wound, which involved the left upper extremity and crossed the elbow joint, was managed with initial debridement followed by a period of local wound care to allow for clearance of infection. We then performed reconstruction in a staged fashion with dermal substitute (Integra, Integra LifeSciences Holdings Corporation, Princeton, NJ) placement and split-thickness skin grafting (STSG). In this case, we demonstrate that the extensive soft tissue infections that may be found in HIES patients can be successfully managed with skin grafting and dermal substitutes.

PMID:40901239 | PMC:PMC12400983 | DOI:10.7759/cureus.89247

Ann Med Surg (Lond). 2025 Jul 15;87(9):6101-6106. doi: 10.1097/MS9.0000000000003591. eCollection 2025 Sep.

ABSTRACT

INTRODUCTION: Zeta-chain-associated protein kinase 70 (ZAP70) is a tyrosine kinase that plays a crucial role in T-cell activation via the T-cell receptor/CD3 complex and contributes to B-cell signaling. ZAP70 variants can cause a range of immunodeficiencies with variable clinical presentations, including infections and malignancies.

CASE PRESENTATION: A 4-year-old boy presented with chronic cough, dyspnea, recurrent chest infections, and failure to thrive. Chest radiography revealed diffuse bilateral opacities, suggesting a diagnosis of diffuse familial bronchiectasis. Immunological workup at 18 years of age showed CD4⁺ and CD8⁺ T-cell lymphopenia, and genetic analysis revealed a homozygous pathogenic ZAP70 splice-site mutation (c.402 + 2 T>C). The patient then developed headaches, dizziness, and double vision, and Epstein-Barr virus (EBV) polymerase chain reaction (PCR) testing revealed a viral load of 700 IU/mL. Magnetic resonance imaging (MRI) revealed three brain lesions, and brain biopsy confirmed EBV-positive CD20 + diffuse large B-cell lymphoma (DLBCL). Despite aggressive chemotherapy and palliative radiotherapy, the patient’s condition deteriorated, resulting in death.

DISCUSSION: To our knowledge, this is the first known case of primary central nervous system DLBCL in a patient with a novel ZAP70 variant. ZAP70 deficiency is typically associated with combined immunodeficiency and rarely with malignancies such as leukemia or lymphoma. Genetic screening at earlier stages could have potentially identified this underlying immunodeficiency sooner and altered the management course.

CONCLUSION: This case underscores the diagnostic challenges and aggressive course of ZAP70-related disease and highlights the need for increased clinical suspicion, immunologic surveillance, early genetic screening, and development of targeted therapies.

PMID:40901120 | PMC:PMC12401455 | DOI:10.1097/MS9.0000000000003591

Investig Clin Urol. 2025 Sep;66(5):448-454. doi: 10.4111/icu.20250221.

ABSTRACT

PURPOSE: Cystoscopy is a commonly performed outpatient urological procedure, with post-procedural urinary tract infections (UTIs) being a key concern. It is generally safe, but high-risk individuals (e.g., diabetics, chronic obstructive pulmonary disease [COPD], immunodeficiency) have a higher risk for potential UTIs. This study evaluates the effectiveness of antibiotic prophylaxis in preventing post-cystoscopy UTIs.

MATERIALS AND METHODS: A prospective observational study was conducted in 2023, enrolling 300 adult patients undergoing ambulatory flexible cystoscopy who were divided into two cohorts: cystoscopy with and without antibiotic prophylaxis. The primary outcome was UTI incidence within four weeks post-procedure, defined by a positive urine culture (>10⁵ CFU/mL) and accompanying symptoms, antibiotic prescriptions, or emergency visits. Positive urine cultures confirmed the primary outcomes.

RESULTS: The study involved 300 patients: 150 received antibiotic prophylaxis (Cohort A), and 150 did not (Cohort B), showing no significant differences in clinical and demographic variables. UTI incidence was 9.3% in Cohort A and 10.0% in Cohort B, with no statistically significant difference (p=0.510). No cases of urinary sepsis were observed. Risk factors such as diabetes, ischemic heart disease, and COPD were evenly distributed across both cohorts.

CONCLUSIONS: Antibiotic prophylaxis did not significantly reduce post-cystoscopy UTI rates. These findings suggest that routine prophylactic antibiotic use may be unnecessary in low-risk patients, reinforcing the need for antibiotic stewardship. Further large-scale studies are warranted to refine clinical guidelines.

PMID:40897663 | DOI:10.4111/icu.20250221

Front Immunol. 2025 Aug 15;16:1645337. doi: 10.3389/fimmu.2025.1645337. eCollection 2025.

ABSTRACT

X-linked agammaglobulinemia (XLA) is a rare primary immunodeficiency disorder caused by mutations in the Bruton tyrosine kinase (BTK) gene. This article presents a fatal case of a 20-year-old male with XLA complicated by septic shock due to Pseudomonas aeruginosa infection, highlighting two novel BTK insertion mutations in exon 15 (NM_000061.3 exon15:c.1561insG and c.1565insTAGAA). Concurrently, we provide a systematic review of XLA’s genetic basis, clinical manifestations, diagnostic challenges, and therapeutic advancements. The patient’s delayed diagnosis, lack of immunoglobulin replacement therapy, and fatal outcome underscore the importance of early genetic screening and standardized management. This case and review aim to enhance clinical awareness and emphasize the integration of genetic diagnostics into routine practice for primary immunodeficiencies.

PMID:40895547 | PMC:PMC12395267 | DOI:10.3389/fimmu.2025.1645337