Research

Expert Rev Clin Immunol. 2025 Sep 16. doi: 10.1080/1744666X.2025.2556435. Online ahead of print.

ABSTRACT

INTRODUCTION: Primary antibody deficiencies (PADs), especially common variable immunodeficiency (CVID), are clinically significant inborn errors of immunity due to complex phenotypes and long-term complications. This review provides an updated overview of pulmonary and gastrointestinal manifestations in PADs, focusing on CVID.

AREAS COVERED: We conducted a structured literature review of original articles, reviews, and guidelines from the last 10 years, using databases such as PubMed and Scopus. The focus was on immunopathogenesis, clinical features, and treatment of noninfectious pulmonary and gastrointestinal complications in CVID. Key shared immunological pathways include B- and T-cell dysregulation, cytokine-driven inflammation, and microbiota alterations.

EXPERT OPINION: Early recognition of noninfectious complications in CVID is vital to prevent organ damage and improve outcomes. A multidisciplinary, personalized approach involving genetic, immunologic, and microbiologic assessments and specialists including pathologists, pulmonologists, and gastroenterologists is essential, considering the pulmonary-gastrointestinal axis’s role in mucosal immune dysfunction and systemic immune dysregulation.

PMID:40957411 | DOI:10.1080/1744666X.2025.2556435

J Periodontal Res. 2025 Sep 16. doi: 10.1111/jre.70034. Online ahead of print.

ABSTRACT

This paper provides a detailed analysis of systemic diseases associated with periodontal tissue loss, focusing on their clinical presentation and etiopathogenesis. It also introduces a framework for categorizing these diseases according to their principal pathological pathways and their periodontal effects. Periodontitis arises from a disruption of host-microbe homeostasis, which leads to a dysbiotic microbiota, chronic inflammation, and subsequent periodontal tissue loss. Complex systemic diseases, particularly those causing systemic inflammation or having an autoimmune component (e.g., diabetes mellitus, osteoporosis, arthritis, and inflammatory bowel disease), can exacerbate pre-existing periodontal inflammation and cause further tissue loss. As their inflammatory and pathological pathways are intertwined with periodontitis, their periodontal manifestations are not considered distinct forms of the disease. In contrast, other systemic diseases disrupt host-microbe homeostasis by causing specific defects in the immune response, whereas others impair tissue metabolism or disrupt the physiology and integrity of epithelial and connective tissues. These diseases can lead to significant periodontal destruction and are considered distinct forms of periodontitis. Examples include Down syndrome, leukocyte adhesion deficiency syndromes, Papillon-Lefèvre syndrome, Haim-Munk syndrome, Chediak-Higashi syndrome, neutropenia, primary immunodeficiency diseases, Cohen syndrome, glycogen storage diseases, Gaucher disease, hypophosphatasia, hypophosphatemic rickets, Hajdu-Cheney syndrome, epidermolysis bullosa, hypoplasminogenemia, and Ehlers-Danlos syndrome. A third category encompasses diseases that induce periodontal tissue loss through mechanisms independent of periodontitis. Examples of this group include Langerhans cell histiocytosis, hyperparathyroidism, and giant cell granulomas. In conclusion, systemic diseases contribute to periodontal tissue loss through overlapping inflammatory pathways, immune dysfunction, or other independent mechanisms. Grouping these diseases by their primary pathological pathways offers a clearer understanding of their effect on periodontal health. This framework may also help direct research toward uncovering shared and unique mechanisms of systemic disease-related periodontal pathology, potentially leading to more targeted therapies and improved disease management.

PMID:40956006 | DOI:10.1111/jre.70034

Leukemia. 2025 Sep 15. doi: 10.1038/s41375-025-02771-8. Online ahead of print.

ABSTRACT

GATA2 deficiency is a monogenic transcriptopathy disorder characterized by bone marrow failure (BMF), immunodeficiency, and a high risk of developing myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Although informative mouse models have been developed, the mechanisms by which GATA2 haploinsufficiency drives disease initiation in humans remain incompletely understood. To address this, we developed a novel humanized model using CRISPR/Cas9 technology to knock-in GATA2-R398W variant in primary cord blood CD34⁺ cells. Additionally, we introduced specific mutations in SETBP1 and ASXL1 to model distinct premalignant stages of GATA2 deficiency. Through clonal competition and serial transplantation assays, we demonstrated that human CD34⁺ cells harboring the GATA2 mutation exhibit significantly reduced fitness in vivo when compete with wild-type cells. Notably, this fitness disadvantage persists even when GATA2 mutations are combined with oncogenic SETBP1 and ASXL1 drivers, underscoring the dominant, deleterious effect of GATA2 deficiency on hematopoietic stem cell function. Functional in vitro analyses revealed that GATA2-R398W mutation impairs cell proliferation, disrupts cell cycle progression, and induces mitotic defects, which may contribute to hematopoietic stem/progenitor cell loss and impaired self-renewal. Transcriptomic profiles of GATA2-mutant cells revealed that these functional defects are associated with reduced HSC self-renewal capacity and upregulation of the pre-aging phenotype. Our work highlights the feasibility of generating a human GATA2 deficiency model suitable for studying the biological consequences of various GATA2 variants and the generation of a platform to test potential phenotype-rescuing therapeutics.

PMID:40954215 | DOI:10.1038/s41375-025-02771-8

iScience. 2025 Jul 7;28(8):113072. doi: 10.1016/j.isci.2025.113072. eCollection 2025 Aug 15.

ABSTRACT

Neutrophils are essential immune cells loaded with cytosolic granules that contain potent antimicrobial and immunostimulatory molecules. Alterations of neutrophil granule contents are associated with immunodeficiency and hyperinflammation. Identification of regulators of granule development can aid in understanding of neutrophil-driven pathologies. Here, we perform a systematic prioritization of genetic variants associated with neutrophil cytometric side scatter (SSC), a proxy for granularity, identified in a genome-wide association study (GWAS) of blood parameters in healthy individuals. We show that triangulation of GWAS data with epigenetic and eQTL data identifies previously unknown factors regulating neutrophil granularity. We validate this approach using cellular and animal models to confirm that cyclin dependent kinase 6 (encoded by CDK6) regulates neutrophil granule development. CDK6 specifically regulates the abundance of primary granules without affecting neutrophil maturation. Our approach demonstrates the utility of cell counter-derived SSC data paired with genomics as a tool to investigate neutrophil development and function.

PMID:40948552 | PMC:PMC12432455 | DOI:10.1016/j.isci.2025.113072

J Thorac Dis. 2025 Aug 31;17(8):5883-5892. doi: 10.21037/jtd-2025-283. Epub 2025 Aug 15.

ABSTRACT

BACKGROUND: Pulmonary aspergilloma is a chronic fungal infection that can cause life-threatening massive hemoptysis or deteriorate into invasive fungal disease. Unilateral lung transplant recipients (LTRs) are at particular risk for developing this complication in their pathological native lung. This study aims to describe our experience with native lung aspergilloma, its management, and outcomes.

METHODS: We collected a series of cases of native lung aspergilloma based on a retrospective chart review of all patients who underwent single lung transplantation (SLT) at Rabin Medical Center between November 1997 and March 2023.

RESULTS: In our cohort of 911 LTRs, 465 underwent SLT. The primary diagnoses were chronic obstructive pulmonary disease (COPD) in 166 patients (35%) and idiopathic interstitial pneumonia in 261 patients (56%). Five patients were identified with native lung aspergilloma, all with interstitial lung disease (ILD) as the primary diagnosis. The median time from transplantation to aspergilloma diagnosis was 45 months. Four patients received conservative treatment with antifungal therapy; three are alive with a median follow-up of 62 months, one of whom is being evaluated for surgical intervention. One patient died within 6 months, likely due to Aspergillus infection. Another patient underwent a successful pneumonectomy and survived for more than 8 years.

CONCLUSIONS: This case series emphasizes the importance of a high index of suspicion of aspergilloma developing in the native lung after an SLT. Although this is a significantly high-risk group due to their immunodeficiency, their overall prognosis in our study remains similar to that of non-immunocompromised patients.

PMID:40950912 | PMC:PMC12433020 | DOI:10.21037/jtd-2025-283

Cureus. 2025 Aug 12;17(8):e89898. doi: 10.7759/cureus.89898. eCollection 2025 Aug.

ABSTRACT

Hyper-immunoglobulin E syndrome (HIES) and idiopathic eosinophilia lie on the same spectrum of immunodeficiency disease; therefore, physicians need to consider both possibilities as differential diagnoses for early identification. HIES is a primary immunodeficiency syndrome characterized by markedly elevated total IgE levels along with recurrent eczematous rash, skin infections, sinopulmonary infections, and multiple hospitalizations. Similarly, patients with idiopathic hypereosinophilic syndrome (HES) also present with marked eosinophilia, recurrent sinopulmonary infections, and evidence of organ damage such as eosinophilic myositis. Idiopathic eosinophilia also lacks any identifiable secondary aetiology and evidence of organ damage, with only eosinophilia in bone marrow. Both our cases have similar symptoms, presenting in the busy outpatient department settings that needed thoughtful consideration for the differentials. Awareness among Clinicians about this wide spectrum of differentials with overlapping presentations will facilitate early diagnosis and eventually enable optimal cost-effective treatment for patients.

PMID:40951244 | PMC:PMC12424829 | DOI:10.7759/cureus.89898

J Allergy Clin Immunol Pract. 2025 Sep;13(9):2460-2474. doi: 10.1016/j.jaip.2025.06.015.

ABSTRACT

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are rare genetic disorders impairing immunity. Studies evaluating diagnostic rates of PIDDs in historically marginalized US populations are limited.

OBJECTIVE: To conduct a scoping review that identifies the extent of race and ethnicity reporting in US-based observational studies of people with PIDDs, and the demographic composition of study populations compared with the broader US population.

METHODS: We conducted pragmatic searches of MEDLINE in April 2024 and ultimately included studies dating back 10 years. Results were screened and extracted against prespecified eligibility criteria by a single reviewer. Included data were compared with US census data using χ² tests.

RESULTS: We identified 126 publications publishing observational PIDD studies that report patient characteristics, 62 of which (49%) reported race or ethnicity data. After grouping for data source and PIDD type to avoid overlapping studies, 25 publications were prioritized for extraction. Of these, seven were fully compliant with current Food and Drug Administration-recommended reporting guidelines. The populations of the extracted studies were not statistically representative of the broader US population, with overrepresentation of non-Hispanic White patients.

CONCLUSIONS: Primary immunodeficiency disease cohort and other studies inconsistently report demographic data on patient race and ethnicity according to current Food and Drug Administration recommendations. Efforts to improve understanding of the prevalence, characteristics, and diagnostic rates of PIDD in different US populations (as well as differences among study populations and overall US demographics) would likely be facilitated by a greater effort toward comprehensive demographic reporting.

PMID:40947178 | DOI:10.1016/j.jaip.2025.06.015

Immunol Cell Biol. 2025 Sep 14. doi: 10.1111/imcb.70058. Online ahead of print.

ABSTRACT

Activated PI3K delta syndrome 1 (APDS1) is caused by a heterozygous germline gain-of-function (GOF) variant in PIK3CD, which encodes the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K). APDS1 patients display a broad range of clinical manifestations and perturbations in cellular phenotype. One of the most striking features is the dysregulation of the T-cell compartment, characterized by an increase in memory T cells, including Tfh cells, and a concomitant decrease in naïve T cells. We have previously shown that many of these changes in T-cell populations were T-cell extrinsic and were also induced in WT T cells that developed in the presence of PI3K GOF cells. Here we dissected the drivers of dysregulated T-cell activation using a mouse model of APDS1. This revealed that PI3K GOF macrophages and DCs made little contribution to the aberrant T-cell activation. Instead, PI3K GOF T cells were able to drive the loss of WT naïve CD4⁺ T cells, while dysregulated PI3K GOF B cells mediated an increase in Tfh cells. Surprisingly, despite previous reports of increased PI3K signalling driving dysregulated inflammatory Tregs, we saw no evidence for Pik3cd GOF Tregs acquiring an inflammatory phenotype and driving T-cell activation. These studies provide new insights into the role of PI3K in immune cells and how increased PI3K can drive T- and B-cell dysregulation and contribute to the phenotype of APDS1 patients.

PMID:40946708 | DOI:10.1111/imcb.70058

J Clin Med. 2025 Aug 23;14(17):5958. doi: 10.3390/jcm14175958.

ABSTRACT

Background: Inborn errors of immunity (IEI) are mainly genetically driven disorders that affect immune function and present with highly heterogeneous clinical manifestations, ranging from severe combined immunodeficiency (SCID) to adult-onset immune dysregulatory diseases. This clinical heterogeneity, coupled with limited awareness and the absence of a universal diagnostic test, makes early and accurate diagnosis challenging. Although genetic testing methods such as whole-exome and genome sequencing have improved detection, they are often expensive, complex, and require functional validation. Recently, artificial intelligence (AI) tools have emerged as promising for enhancing diagnostic accuracy and clinical decision-making for IEI. Methods: We conducted a systematic review of four major databases (PubMed, Scopus, Web of Science, and Embase) to identify peer-reviewed English-published studies focusing on the application of AI techniques in the diagnosis and treatment of IEI across pediatric and adult populations. Twenty-three retrospective/prospective studies and clinical trials were included. Results: AI methodologies demonstrated high diagnostic accuracy, improved detection of pathogenic mutations, and enhanced prediction of clinical outcomes. AI tools effectively integrated and analyzed electronic health records (EHRs), clinical, immunological, and genetic data, thereby accelerating the diagnostic process and supporting personalized treatment strategies. Conclusions: AI technologies show significant promise in the early detection and management of IEI by reducing diagnostic delays and healthcare costs. While offering substantial benefits, limitations such as data bias and methodological inconsistencies among studies must be addressed to ensure broader clinical applicability.

PMID:40943725 | DOI:10.3390/jcm14175958

Sci Rep. 2025 Sep 12;15(1):32442. doi: 10.1038/s41598-025-17139-2.

ABSTRACT

Seroma formation is a frequent complication following mastectomy in the surgical treatment of breast cancer with profound consequences for the patients including possibly quality of life impairing implant complications. The pathogenesis remains unknown, leading to a lack of efficient preventive and curative strategies. The study’s objective was to determine whether the macrophage infiltration of the tumor microenvironment and surrounding adipose tissue at the time of primary surgery is associated with postoperative seroma development. The observational monocentric SerMa pilot study was conducted from 12/2019 to 12/2022. We included 91 breast cancer and 9 carcinoma in situ cases treated with mastectomy at the University Hospital Augsburg, Germany. Patients with previous malignancies, metastatic disease and known immunodeficiency were excluded. The patients underwent different mastectomy procedures with or without implant- or expander-based breast reconstruction. The study’s main outcome was seroma formation up to six months post-surgery, determined by clinical examination and fine needle aspiration of the seroma fluid if clinically necessary. Macrophage markers (CD68 and CD163) were immunohistochemically determined in formalin fixed paraffin-embedded slides containing the primary tumor and surrounding adipose tissue. Two groups were then formed as independent variables: cases with (seroma +) and without postoperative seroma formation (seroma-). Since all parameters in this study were not normally distributed, the non-parametric Mann-Whitney-U-test was used. A p-value < 0.05 was considered statistically significant. CD68 + cells (cases with seroma (seroma +): median = 90.7 cells, IQR = 62.5-130.5; cases without seroma (seroma-): median = 64.3 cells, IQR = 47.0-115-0, p = 0.036) and CD163 + cells (seroma + : median = 58.3 cells, IQR = 33.0-91.4; seroma-: median = 40.7 cells, IQR = 28.3-55.3, p = 0.027) in the tumor microenvironment and in the surrounding adipose tissue (CD68 + cells (seroma + : median = 8.0 cells, IQR = 5.3-11.0; seroma-: median = 4.7 cells, IQR = 3.0-10.0, p = 0.013), CD163 + cells (seroma + : median = 11.0 cells, IQR = 6.7-15.0; seroma-: median = 6.7 cells, IQR = 3.0-9.7, p = 0.016)) were significantly higher in cases with postoperative seroma formation compared to cases without. In the SerMa pilot study macrophage polarization within the primary tumor and surrounding adipose tissue was associated with post-operative seroma formation in breast cancer patients. This might be a suitable biomarker for predicting a higher risk of seroma formation.

PMID:40940394 | DOI:10.1038/s41598-025-17139-2