Research

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

J Hum Immun. 2025 Dec 17;2(1):e20250163. doi: 10.70962/jhi.20250163. eCollection 2026 Jan 5.

ABSTRACT

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for severe combined immunodeficiency (SCID). Since the initiation of newborn screening (NBS), survival rates have improved significantly, but the impact of HCT upon neurodevelopment for patients with SCID requires more investigation. We performed a cross-sectional study of subjects with SCID in North America to assess the impact of NBS, transplant conditioning regimen, and genotype on neurodevelopmental outcomes after HCT. 69 subjects with SCID from 17 PIDTC centers (excluding those with ADA deficiency), ages 6-16 years, received comprehensive standardized neurodevelopmental testing of cognitive, behavioral, and emotional function. Compared with the normative population, our subjects performed in the average range. We found no impact of NBS, chemotherapy conditioning, or genotype. Multivariate analysis revealed a significant decrease in IQ in subjects whose families earned <$50,000 per year. We recommend that children treated by HCT for SCID be monitored with periodic cognitive and behavioral assessments for deficits that could potentially impact long-term ND outcomes.

PMID:41608119 | PMC:PMC12829746 | DOI:10.70962/jhi.20250163

Clin Chem. 2026 Jan 29:hvaf190. doi: 10.1093/clinchem/hvaf190. Online ahead of print.

ABSTRACT

BACKGROUND: Primary immunodeficiencies (PIDs) are rare disorders caused by immune system defects that are commonly screened using multi-parameter flow cytometry (FCM). To counter the subjective and time-consuming manual data analysis of FCM data, we present PIDgeon, a fully automated computational pipeline based on artificial intelligence (AI) techniques. PIDgeon is designed to characterize PID immune profiles, suggest PID subtypes based on altered immune profiles, age, and immunoglobulin levels, and generate interpretable reports.

METHODS: The PIDgeon pipeline, including FlowSOM and extreme gradient boosting models, was trained and tested on standardized FCM data generated according to EuroFlow procedures on 74 healthy controls and 399 patients (281 lymphoid-PID patients and 118 non-PID diseased controls) collected by the Ghent University Hospital. Subsequently, multi-centric validation was performed on internal (n = 211) and external (n = 338) independent data sets collected across 4 EuroFlow centers.

RESULTS: Validation demonstrated high accuracy in cell count enumeration, achieving correlation scores above 0.90 for the major lymphocyte subsets. Interestingly, PIDgeon showed high sensitivity (93% to 100%) in predicting PID with severe T-cell defects, such as severe combined immunodeficiency and late-onset combined immunodeficiency, and low false-negative rates (1.5% to 5.4%) for distinguishing other lymphoid-PID vs non-PID diseased controls across data sets. Additionally, PIDgeon gives a first hint toward prediction of subtypes of primary antibody deficiencies, such as common variable immunodeficiency.

CONCLUSIONS: In summary, PIDgeon is an accessible and explainable AI-pipeline aligned with current clinical needs, aiding laboratory immunologists in early PID diagnostics and increasing data analysis efficiency.

PMID:41605242 | DOI:10.1093/clinchem/hvaf190

J Exp Med. 2026 Mar 2;223(3):e20241707. doi: 10.1084/jem.20241707. Epub 2026 Jan 28.

ABSTRACT

Patients with loss-of-function DOCK8 or dominant-negative STAT3 variants have hyper-IgE syndrome, although only DOCK8 deficiency consistently presents with elevated food-specific IgE and symptomatic allergy. We previously found in mice that DOCK8 restricts the differentiation of IL-13+ T follicular helper (Tfh13) cells that drive anaphylactic IgE, although the mechanisms were unclear. Here, we show that DOCK8 promotes STAT3 activity, which inhibits GATA3 in T cells. However, only patients with DOCK8, but not STAT3, deficiency had elevated Tfh13 cells. Cell-specific deletion of either Dock8 (T-Dock8-/-) or Stat3 (T-Stat3-/-) augmented peanut-specific IgE and Tfh13s when oral sensitization was promoted by adjuvants. However, the phenotypes diverged during adjuvant-free oral peanut exposure: only T-Dock8-/- mice developed Tfh13 cells and peanut-specific IgE, accompanied by reduced Foxp3+ Tregs. Treg depletion in T-Stat3-/- mice unmasked Tfh13 induction to oral antigen alone. Thus, DOCK8 and STAT3 cooperate to restrain Tfh13 differentiation to food allergens, and additional Treg impairment in DOCK8 deficiency allows for Tfh13 cell induction and allergy.

PMID:41604592 | DOI:10.1084/jem.20241707

Front Immunol. 2026 Jan 12;16:1708366. doi: 10.3389/fimmu.2025.1708366. eCollection 2025.

ABSTRACT

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare but fatal blood transfusion complication, with a mortality rate of 90-100%. Severe combined immunodeficiency (SCID) is a life-threatening primary immunodeficiency with profound cellular and humoral defects. Patients with SCID are highly susceptible to TA-GVHD. Here, we report a 4-month-old male admitted for sepsis and severe pneumonia, with pustular rash and unhealed exudative Bacillus Calmette-Guérin vaccination site. Laboratory tests showed hypogammaglobulinemia and lymphopenia. Lymphocyte subset analysis confirmed the presence of T-B+NK immunodeficiency. Mycobacterium bovis complex was detected in blood, while rifampicin-resistant Mycobacterium tuberculosis complex was identified in sputum and ascitic fluid. Whole-exome and Sanger sequencing identified a novel interleukin-2 receptor common gamma chain (IL2RG) nonsense mutation [NM_000206.3: c.865C>T, p.(Arg289Ter)]. To the best of our knowledge, this specific IL2RG mutation has not been previously reported. On the 33rd day of admission, the infant accidentally received non-irradiated leucoreduced red blood cells, then developed typical TA-GVHD manifestations including fever, hepatomegaly, rash and diarrhea, and high-resolution Human Leukocyte Antigen typing confirmed it. The parents chose to terminate treatment on the 69th day of admission, and the patient died after discharge. The dynamic evolution of clinical manifestations and laboratory tests in this patient is described, along with a review of the relevant literature. This report expands the mutational spectrum of IL2RG and reveal the reference value of peripheral blood lymphocyte and eosinophil counts for early TA-GVHD identification.

PMID:41601678 | PMC:PMC12832548 | DOI:10.3389/fimmu.2025.1708366