Research

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

Int J Infect Dis. 2026 Jan 25:108438. doi: 10.1016/j.ijid.2026.108438. Online ahead of print.

ABSTRACT

BACKGROUND: Anti-interferon-γ autoantibody syndrome (AIGAs) is a primary immunodeficiency disorder characterized by neutralizing autoantibodies blocking IFN-γ signaling, predisposing patients to severe opportunistic infections. No definitive treatment protocol exists, and conventional therapies carry infection risks. Hemoadsorption (HA) is effective for autoimmune diseases but has not been specifically investigated for AIGAs.

CASE PRESENTATION: A 65-year-old Chinese female was admitted with 10-month painless disseminated lymphadenopathy. 18F-FDG PET/CT showed multiple hypermetabolic lymph nodes, and ultrasound-guided biopsy revealed necrotizing granulomatous inflammation. Metagenomic next-generation sequencing (mNGS) identified Mycobacterium abscessus, and ELISA confirmed high AIGA levels (88.05% at 1:3200 dilution). She received anti-nontuberculous mycobacteria (NTM) therapy (clarithromycin, minocycline, contezolid) combined with one HA session using a cytokine adsorption column. Post-treatment, AIGA levels normalized to 0% at 24 weeks and remained stable. 72-week follow-up showed resolved lymphadenopathy and reduced lymph node size/metabolic activity on PET/CT.

CONCLUSION: This is the first report of single-session HA for AIGAs complicated by disseminated Mycobacterium abscessus infection. HA effectively reduced AIGA levels, controlled infection, and avoided global immunosuppression, providing a promising adjunctive therapy for AIGAs patients with severe disseminated infections.

PMID:41592665 | DOI:10.1016/j.ijid.2026.108438

Allergy Asthma Immunol Res. 2026 Jan;18(1):132-144. doi: 10.4168/aair.2026.18.1.132.

ABSTRACT

PURPOSE: The impact of coronavirus disease 2019 (COVID-19) on patients with primary immunodeficiency (PID) remains insufficiently characterized. This study aimed to describe the clinical manifestations, disease course, and outcomes of COVID-19 in patients with PID.

METHODS: Adult patients with PID who had COVID-19 infection between March 2020 and August 2022 were screened. Demographic and clinical data were retrospectively collected from institutional databases, and additional information was obtained through a patient questionnaire.

RESULTS: A total of 36 patients (19 males, 17 females; median age: 36.5 years) with various PID subtypes were included: 24 with common variable immunodeficiency (CVID), 3 with cytotoxic T-lymphocyte-associated protein-4 haploinsufficiency, 3 with X-linked agammaglobulinemia (XLA), 2 with hypogammaglobulinemia, 1 with lipopolysaccharide-responsive and beige-like anchor protein deficiency, 1 with DiGeorge syndrome, 1 with mitochondrial neurogastrointestinal encephalomyopathy syndrome, and 1 with CVID-like capillary malformation-arteriovenous malformation syndrome 2. Overall, 63.9% (n = 23) were managed as outpatients, while 36.1% (n = 13) required hospitalization. Admission to the intensive care unit was required in 19.4% (n = 7) of the cases. The overall case fatality rate was 8.3% (n = 3), which is higher than the rate observed in the general population. Although the majority experienced a mild clinical course, patients with XLA exhibited prolonged symptoms and persistent seropositivity. Risk factors associated with hospitalization included lymphopenia, elevated C-reactive protein and ferritin levels, dyspnea, COVID-19 Reporting and Data System score ≥ 4 on imaging, need for supplemental oxygen, prolonged symptoms, and extended polymerase chain reaction positivity.

CONCLUSIONS: A subset of adult patients with PID may be at increased risk for severe COVID-19.

PMID:41592542 | DOI:10.4168/aair.2026.18.1.132

Ophthalmol Sci. 2025 Dec 3;6(2):101027. doi: 10.1016/j.xops.2025.101027. eCollection 2026 Feb.

ABSTRACT

PURPOSE: To evaluate conventional imaging modalities for detecting fibrosis in neovascular age-related macular degeneration (nAMD) and to develop a standardized diagnostic workflow.

DESIGN: Systematic discussion and grading exercise assessing multiple imaging modalities.

PARTICIPANTS: Retina specialists from the International Fibrosis Consensus workgroup and members of the International Retinal Imaging Society.

METHODS: An international panel assessed the advantages and limitations of 5 imaging modalities-color fundus photography (CFP), fluorescein angiography (FA), spectral domain OCT (SD-OCT), near-infrared reflectance, and fundus autofluorescence-for detecting fibrosis in nAMD. A structured debate was followed by 2 online, masked image grading surveys. Sensitivity, specificity, and predictive accuracy of each modality, alone and in combination, were determined. Intergrader agreement was calculated. Imaging features were also correlated with histology in a nonhuman primate laser model. Based on consensus discussions at 2 in-person meetings and survey results, a 2-step diagnostic approach using SD-OCT as the primary modality was proposed.

MAIN OUTCOME MEASURES: Recommendation for a standardized approach for diagnosing fibrosis in eyes with nAMD.

RESULTS: Among the 5 modalities, SD-OCT was considered essential by all workgroup members. Hyperreflective material on OCT was unanimously identified as a key indicator of fibrosis. However, its limited specificity was acknowledged. In 2 masked grading exercises, SD-OCT showed the highest sensitivity (0.88 and 0.84) but only moderate specificity (0.56 and 0.57). The area under the curve (AUC) for SD-OCT was 0.72 and 0.70. A 2-step strategy combining SD-OCT with CFP or FA improved diagnostic accuracy. Hyperreflective material was defined as material with reflectivity equal to or greater than normal retinal pigment epithelium (RPE), well-defined margins, RPE disruption, and a laminated appearance. Corresponding CFP findings included well-defined yellow/white/gray subretinal lesions, and FA findings included early blocked fluorescence and late staining. This 2-step approach increased AUC to 0.85, with sensitivity of 0.83 and specificity of 0.87.

CONCLUSIONS: The study establishes a 2-step approach using OCT as the primary modality in clinical studies for the detection of fibrosis.

FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PMID:41584096 | PMC:PMC12830330 | DOI:10.1016/j.xops.2025.101027

Front Immunol. 2026 Jan 8;16:1735023. doi: 10.3389/fimmu.2025.1735023. eCollection 2025.

ABSTRACT

INTRODUCTION: This study aims to present in a large real-world cohort a diagnostic algorithm developed to facilitate the early recognition of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS), a rare disease with targeted treatment options, and to provide clinicians with a practical roadmap for navigating diagnostic challenges.

METHODS: The study was conducted as a retroactive cross-sectional observational study. We reviewed the medical records of 6,458 pediatric and adult patients who were referred to our clinic between 2018 and 2025. A medical algorithm was generated based on major clinical and laboratory features of APDS. Next-generation sequencing analyses were performed on patients who were appropriate for further evaluation. Variant analysis using in silico predictors and S6 phosphorylation analysis in patients carrying previously undescribed variants were conducted accordingly.

RESULTS: In this cohort of 6,458 patients, the diagnostic algorithm identified 1,138 who met at least one major clinical or laboratory criterion. After excluding 7 with a prior APDS diagnosis and 573 with other inborn errors of immunity, genetic analysis was performed in 20 consenting patients under clinical follow-up (11 [55%] female, 9 [45%] male; median age 15 years; IQR 7.5-24). APDS type 2 was confirmed in 1 patient; five others harbored novel variants of uncertain significance.

CONCLUSION: Delayed diagnosis and treatment of APDS may result in life-threatening complications and irreversible end-organ damage. Given its heterogeneous, overlapping phenotype, timely referral for genetic testing is essential.

PMID:41583441 | PMC:PMC12823944 | DOI:10.3389/fimmu.2025.1735023

Hum Pathol. 2026 Jan 22:106051. doi: 10.1016/j.humpath.2026.106051. Online ahead of print.

ABSTRACT

BACKGROUND: Primary central nervous system immunodeficiency/dysregulation-associated lymphoproliferative disorders (PCNS-IDD-LPDs) are a rare and heterogeneous group of lymphoid lesions that arise within the CNS of immune compromised patients. Among PCNS-IDD-LPDs, monomorphic IDD-LPDs are relatively well studied; however, data regarding PCNS polymorphic IDD-LPDs is very limited. It remains unclear whether polymorphic PCNS IDD-LPDs follow a similarly indolent clinical course as observed in their systemic polymorphic counterparts, or whether the unique immune microenvironment of the CNS imparts a more aggressive disease biology.

METHODS: In this study, we compared the clinical, pathologic, and survival profile of PCNS polymorphic IDD-LPDs (N=15) with extra-CNS polymorphic IDD-LPDs (N=21) as well as PCNS monomorphic IDD-LPDs (N=12).

RESULTS: Compared to extra-CNS polymorphic IDD-LPDs, patients with PCNS polymorphic IDD-LPDs showed a significantly stronger association with kidney transplants, longer latency, worse performance status, more frequent monoclonal populations and necrosis, and a greater need for aggressive chemoimmunotherapy in addition to reduction in immunosuppression and/or rituximab. The overall survival (OS) of PCNS polymorphic IDD-LPDs was significantly inferior to that of extra CNS polymorphic IDD-LPDs (median survival: 7.1 years vs. not reached; log-rank p=0.023) and not significantly different from PCNS monomorphic IDD-LPDs (median survival: 7.1 vs. 3.6 years; log-rank p=0.852).

CONCLUSION: We conclude that PCNS polymorphic IDD-LPDs have a uniquely aggressive clinicopathologic and prognostic profile compared to their systemic counterparts and are comparable to their monomorphic PCNS counterparts. CNS localization supersedes the histological subtype as the primary determinant of disease biology in IDD-LPDs, likely ascribed to the immune sanctuary status of the CNS.

PMID:41580209 | DOI:10.1016/j.humpath.2026.106051

Scand J Immunol. 2026 Feb;103(2):e70092. doi: 10.1111/sji.70092.

ABSTRACT

Jeffrey Modell warning signs have been used to guide screening for inborn errors of immunity (IEIs) for over three decades now, but may lack sensitivity for noninfectious presentations. Our study explored JMF signs along with additional signs and some laboratory parameters and assessed their effectiveness for guiding molecular screening for IEIs. We retrospectively analysed 100 patients suspected of IEI referred to ICMR-National Institute of Immunohaematology from immunology clinics who underwent whole-exome sequencing (WES), with pathogenic (n = 50) and no variants (n = 50). We evaluated clinical presentations other than JMF-autoimmunity, autoinflammation, vaccine complications, fever with bi-cytopenia, consanguinity and laboratory parameters-absolute lymphocyte count, low naïve T cell (%) and hypogammaglobulinaemia at initial presentation. Thirty-two models with different combinations of additional signs along with JMF score were evaluated based on the AIC score to determine the best model. The model was validated on WES results of 219 patients. The JMF scores of the pathogenic/likely pathogenic group (3.54 ± 1.92) were significantly higher than those of the no variants group (1.34 ± 1.28) (p < 0.05). The best model, inclusive of consanguinity, presence of autoimmunity, vaccine complications, hypogammaglobulinaemia and low naïve T cell (%) with JMF, had a sensitivity and specificity of 82% and 67%, respectively, compared to sensitivity and specificity of 84% and 61% for JMF alone. Our study shows that the presence of any two among parental consanguinity, presence of autoimmunity, vaccine complications and low naïve T cell (%) improves the specificity of JMF criteria in guiding molecular screening for IEIs.

PMID:41580301 | DOI:10.1111/sji.70092