Research

Life Med. 2025 Nov 25;4(5):lnaf030. doi: 10.1093/lifemedi/lnaf030. eCollection 2025 Oct.

ABSTRACT

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a primary immunodeficiency characterized by hyperactivated lymphocytes and recurrent infections. This study presents a 2.5-year-old patient with a novel PIK3CD gene mutation (c.1309C>T; p. R437C) derived from his mother. We explored the immunological consequences of this mutation in both the patient and his mother, revealing defects in T cell differentiation, B cell maturation, and mitochondrial function. Notably, we found that the elevated CD38 expression on B cells is a key factor driving B cell senescence, mitochondrial dysfunction, and increased transitional B cell proportion, contributing to the observed immunodeficiency, such as diminished serum antibodies. Further investigations of the PI3K/AKT/mTOR pathway highlight a preferential activation of mTORC2 over mTORC1. We also demonstrate that the transcription factor FOXO1, a downstream molecule of PI3K/AKT signaling, regulates CD38 expression by binding to the promotor of the CD38 gene, linking this pathway to B cell dysfunction. This novel mutation expands the spectrum of PIK3CD mutations associated with APDS and provides new insights into the molecular mechanisms underlying B-cell senescence and other immune dysregulation. Moreover, targeting the AKT-FOXO1 axis could offer therapeutic potential to reverse B-cell dysfunction and improve immune responses in patients with PIK3CD mutations.

PMID:41626283 | PMC:PMC12853000 | DOI:10.1093/lifemedi/lnaf030

BMC Pulm Med. 2026 Jan 31. doi: 10.1186/s12890-026-04115-3. Online ahead of print.

ABSTRACT

BACKGROUND: Combined immunodeficiency (CID) involves profound defects in B and T lymphocyte development and function. This study examined clinical and immunological phenotypes of CID patients with and without pulmonary manifestations.

METHODS: This retrospective multicenter study included 53 CID patients diagnosed between 2009 and 2022 with available thoracic computed tomography scans. Patients were categorized based on pulmonary manifestations presence. Demographic, clinical, and laboratory characteristics were compared using conservative statistical thresholds (P < 0.01). All laboratory parameters were interpreted using age-adjusted pediatric reference ranges.

RESULTS: Among 53 patients (56.6% male), 43 had pulmonary abnormalities on HRCT. Common clinical features included skin lesions (43.4%), failure to thrive (34%), and autoimmunity (32.1%). HRCT revealed pneumonia (28.3%), bronchiectasis (18.9%), interstitial lung disease with BOOP-like pattern (3.8%), and other findings. Using age-adjusted pediatric reference ranges, profound immunological defects were confirmed: absolute lymphocyte count below the 5th percentile in 92% (49/53), CD3 + T cells below the 5th percentile in 94% (47/50 tested), CD4 + T cells below the 5th percentile in 96% (51/53), CD19 + B cells below the 5th percentile in 94% (50/53), and hypogammaglobulinaemia (IgG below the 5th percentile) in 98% (52/53). Patients with abnormal HRCT had significantly lower CD4 + T-cell counts (178 vs. 498 cells/µL; P = 0.008) and CD19 + B-cell counts (42 vs. 189 cells/µL; P = 0.009). Bronchoscopy identified Aspergillus fumigatus, Streptococcus pneumoniae, and multidrug-resistantAcinetobacter baumannii. Deceased patients showed significantly lower baseline platelets (183,000 vs. 266,000 cells/µL; P = 0.009), IgG (380 vs. 720 mg/dL; P = 0.007), and IgE (0.8 vs. 12 IU/mL; P = 0.008).

CONCLUSION: Pulmonary manifestations affect 81.1% of Iranian CID patients. Low baseline platelets, IgG, and IgE constitute a robust prognostic triad for mortality (P = 0.009, P = 0.007, P = 0.008 respectively). Application of age-adjusted reference ranges revealed profound immunological defects. Systematic HRCT surveillance using low-dose protocols and distinguishing infectious sequelae from immune-mediated lung disease guides targeted management in resource-limited settings.

PMID:41620725 | DOI:10.1186/s12890-026-04115-3

BMJ Open. 2026 Jan 30;16(1):e105768. doi: 10.1136/bmjopen-2025-105768.

ABSTRACT

OBJECTIVE: Across medicine, new therapies are shifting treatment from clinic to home settings. At-home subcutaneous immunoglobulin treatment for immunodeficiency is an example of one such therapy. In this qualitative interview study, we investigated experiences of patients living an everyday life with subcutaneous immunoglobulin at-home treatment.

STUDY DESIGN, SETTING AND PARTICIPANTS: 24 Danish patients participated in semistructured interviews. Six patients were interviewed in individual home-visit interviews, while the remaining 18 participated in one of six subsequent group interviews using an online video format. Participants represented three patient groups: patients with primary immunodeficiency, patients with secondary immunodeficiency, and patients with chronic inflammatory demyelinating polyneuropathy or multifocal motor neuropathy.

RESULTS: According to the interviewed patients, at-home treatment provided a high degree of flexibility and freedom in everyday life. When transitioning to at-home treatment, a sense of security had been achieved through individualised training and access to healthcare professionals. Some patients experienced uncertainty or insecurity during the initial period of administering treatment at home; however, this typically receded over time. For the patients, at-home treatment had become embedded in everyday life either through incorporation into existing everyday routines or through the development of new routines. The time-related and place-related flexibility of the at-home treatment had benefits for several arenas of everyday life: work, family, and leisure. Patients associated at-home treatment with a sense of freedom, which they ascribed both to independence from the hospital and to not being confronted with medical conditions and other patients in the hospital setting. A small minority of the patients viewed the reduced contact with healthcare professionals as a disadvantage, describing feelings of being alone and responsible for their treatment.

CONCLUSIONS: Patients who had established at-home treatment routines in their everyday lives found the benefits of at-home treatment to outweigh the challenges.

PMID:41617229 | DOI:10.1136/bmjopen-2025-105768

J Hum Immun. 2025 Oct 22;1(4):e20250110. doi: 10.70962/jhi.20250110. eCollection 2025 Nov 3.

ABSTRACT

Poikiloderma with neutropenia is a genetic disorder characterized by skin abnormalities, nail dystrophy, bone anomalies, and neutropenia. USB1 encodes a phosphodiesterase essential for processing spliceosomal U6 RNA and some microRNAs, regulating their stability. This study describes a heterozygous de novo USB1 variant (p.P44L) identified in a patient with recurrent infections, hypogammaglobulinemia, and low neutrophil counts. Unlike previously reported mutations, p.P44L affects a conserved proline in the N-terminal domain, predicted to be critical for protein interactions and stability. Functional assays revealed that while U6 RNA processing remained intact, the variant altered protein interactions and subcellular localization, reducing nuclear presence and accumulation within nuclear speckles. In vitro, the variant did not prevent neutrophil differentiation but reduced clonal capacity. In zebrafish, it led to reduced neutrophils and pigmentation. These findings expand the spectrum of genetic traits associated with USB1 and suggest that a heterozygous variant affecting the N-terminal domain of USB1 impacts clinical phenotypes and that hypogammaglobulinemia may be associated with USB1 dysfunction.

PMID:41614062 | PMC:PMC12851572 | DOI:10.70962/jhi.20250110

Curr Issues Mol Biol. 2025 Dec 5;47(12):1016. doi: 10.3390/cimb47121016.

ABSTRACT

Research Subject: Primary and secondary immunodeficiencies represent a growing clinical and public health challenge due to increased susceptibility to infections, impaired immune regulation, chronic inflammation, and disturbances in redox homeostasis. The pathophysiology of these disorders involves dysfunction of innate and adaptive immunity, altered cytokine production, oxidative stress, and reduced activity of antioxidant defense mechanisms. In recent years, attention has increasingly focused on the role of oxidative imbalance and chronic inflammation in weakening immune function. Ozone therapy, when used at controlled low doses, induces a hormetic response that triggers adaptive antioxidant pathways, modulates cytokine profiles, and enhances the activity of immune cells. Due to these properties, ozone has emerged as a potential adjunctive therapy aimed at restoring immune homeostasis and improving clinical outcomes in patients with immune disorders. Aim of Study: The aim of this review is to discuss the role of oxidative stress and immune dysregulation in the pathogenesis of immunodeficiencies and to provide an updated overview of current evidence regarding the therapeutic potential of ozone therapy. This article summarizes molecular mechanisms, biochemical effects, and clinical findings related to ozone-based interventions, with particular emphasis on cytokine modulation, redox balance, macrophage function, regulatory T cells (Treg), and NK cell activity. Materials and Methods: This review is based on scientific data retrieved from PubMed, Scopus, and Google Scholar. Included sources comprise randomized clinical trials, observational studies, meta-analyses, mechanistic studies, and review articles published between 1996 and 2025. Keywords used during the literature search included: “ozone therapy”, “immunomodulation”, “oxidative stress”, “inborn errors of immunity”, “secondary immunodeficiency”, “Treg cells”, “redox homeostasis”. Results: Analysis of current studies shows that controlled low-dose ozone (typically 10-40 µg/mL) activates the Nrf2/ARE antioxidant pathway, increases enzymatic defense (SOD, catalase, GPx), and reduces levels of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. Clinical trials report improved lymphocyte profiles, enhanced macrophage phagocytic function, increased Treg activity, and reinforced NK cell responses. Patients receiving ozone therapy demonstrate reductions in inflammatory markers (CRP, IL-6, D-dimer), improved redox balance, decreased infection frequency, and better overall immune performance. The therapy is generally well tolerated when administered within established safety guidelines. Conclusions: Available evidence indicates that ozone therapy may serve as a valuable adjunct in the management of immunodeficiencies by modulating immune responses, reducing oxidative stress, and restoring homeostatic balance. Although current clinical outcomes are promising, further multicenter randomized trials are needed to standardize dosing protocols, assess long-term effectiveness, and confirm safety.

PMID:41614780 | DOI:10.3390/cimb47121016

J Hum Immun. 2025 Jul 29;1(3):e20250015. doi: 10.70962/jhi.20250015. eCollection 2025 Sep 1.

ABSTRACT

Autosomal dominant STAT1 deficiency is a monogenic defect that increases susceptibility to coccidioidomycosis in humans.

PMID:41607488 | PMC:PMC12829754 | DOI:10.70962/jhi.20250015

Front Immunol. 2026 Jan 13;16:1726673. doi: 10.3389/fimmu.2025.1726673. eCollection 2025.

NO ABSTRACT

PMID:41607792 | PMC:PMC12835365 | DOI:10.3389/fimmu.2025.1726673

J Hum Immun. 2026 Jan 13;2(2):e20250080. doi: 10.70962/jhi.20250080. eCollection 2026 Mar 2.

ABSTRACT

Common variable immunodeficiency (CVID) is a primary antibody defect that leads to frequent infections, but inflammatory complications appear in 30-50%, leading to increased morbidity and mortality. We have previously shown that circulating bacterial 16S ribosomal DNA (rDNA), originating from gut commensals, is significantly increased in the serum of patients with CVID with inflammatory conditions (P = 0.0007). Here we examined the relationships between serum 16S ribosomal DNA (rDNA), isotype-switched memory (SM) B cells, serum IgA, IgA+ SM B cells, serum IFN-γ, and serum B cell-activating factor (BAFF). We found a significant inverse correlation between serum 16S ribosomal DNA (rDNA) concentrations and the numbers of isotype SM B cells, IgA+ SM B cells, and serum IgA levels in our large cohort, suggesting that loss of IgA in the mucosal barrier permits bacterial transcytosis. Loss of SM B cells and lower serum IgA concentrations were both associated with increased serum IFN-γ, as well as increased CXCL9 and serum BAFF concentrations. Serum BAFF was also significantly associated with IFN-γ levels and inversely correlated with baseline serum IgA. We conclude that loss of IgA, accompanied by mucosal defects in CVID, may permit bacterial transcytosis, resulting in excessive IFN-γ and BAFF production, both of which promote autoimmune and inflammatory complications in this immune defect.

PMID:41608052 | PMC:PMC12829748 | DOI:10.70962/jhi.20250080

J Hum Immun. 2025 Apr 15;1(1):e20250002. doi: 10.70962/jhi.20250002. eCollection 2025 May 5.

ABSTRACT

Here, we report the 2024 update of the phenotypic classification by the International Union of Immunological Societies (IUIS) expert committee (EC) on inborn errors of immunity (IEI), which accompanies and complements the 2024 genotypic classification. The aim of this classification is to help diagnosis for clinicians at the bedside and focuses on clinical features and basic laboratory phenotypes of specific IEI. In this update, 559 IEI are described, including 67 novel monogenic defects and 2 new phenocopies. This phenotypic classification is presented in the form of decision trees when possible, with essential clinical or immunological phenotype entries.

PMID:41608113 | PMC:PMC12829316 | DOI:10.70962/jhi.20250002

J Hum Immun. 2025 Apr 15;1(1):e20250003. doi: 10.70962/jhi.20250003. eCollection 2025 May 5.

ABSTRACT

This report provides an updated classification of inborn errors of immunity (IEIs) involving 508 different genes and 17 phenocopies. Of these, we report 67 novel monogenic defects and 2 phenocopies due to neutralizing anti-cytokine autoantibodies or somatic mutations, which either have been discovered since the previous update (published June 2022) or were reported earlier but have been recently confirmed and/or expanded. The new additions were made after rigorous review of new genetic descriptions of IEIs by the International Union of Immunological Societies (IUIS) Expert Committee using criteria established to define IEI. Although similar pathogenic variants in one gene, in terms of both classes of mutation (missense, nonsense, etc.) and impact on protein function, can result in a spectrum of phenotypic manifestations, they are herein classified according to the most consistently reported phenotype. In addition, because different variants in a single gene can result in recognizable diseases due to gain or loss of function, such cases are classified according to their clinical manifestations as a distinct entry in the same or a different table depending on the associated phenotype. This report will serve as a valuable resource for clinical immunologists and geneticists involved in the molecular diagnosis of individuals with heritable and acquired immunological disorders. Moreover, we expect this report to also serve as a valuable resource for all disciplines of medicine, since patients with IEIs may be first seen by rheumatologists, hematologists, allergists, dermatologists, neurologists, gastroenterologists, and pulmonologists, depending upon their spectrum of presenting clinical features. Finally, expanding the known monogenic and related causes of human immune diseases requires dissection of underlying cellular and molecular mechanisms, which reveals fundamental requirements for specific genes, pathways, processes, and even cell types. Such knowledge may not only contribute to improved patient diagnosis and management but also pave the way to the development and implementation of therapies that target the cause-rather than the symptoms-of these conditions.

PMID:41608114 | PMC:PMC12829761 | DOI:10.70962/jhi.20250003