Research

Front Immunol. 2026 Jan 2;16:1701384. doi: 10.3389/fimmu.2025.1701384. eCollection 2025.

ABSTRACT

Inborn errors of immunity (IEI), also known as primary immunodeficiencies, are a heterogeneous group of rare disorders characterized by increased susceptibility to infections, immune dysregulation, and malignancy. Early detection remains a major challenge due to the complexity of clinical presentations, limited awareness among non-specialists, and delayed diagnostic pathways. This review explores current strategies to enhance early detection of IEI, highlighting both technological innovations and clinical insights. Tools such as newborn screening, the Jeffrey Modell Foundation (JMF) warning signs, software like SPIRIT, and the PIDCAP project-a structured model designed for primary care implementation using ICD-coded clinical data- have shown promise in identifying at-risk patients. Artificial intelligence (AI) offers additional potential by detecting diagnostic patterns in electronic health records, although challenges related to data quality, heterogeneity, and system interoperability persist. Importantly, hematologic manifestations such as autoimmune cytopenias, lymphoproliferative disorders, and myelodysplastic syndromes often precede or accompany IEI and should prompt immunological evaluation. These conditions, frequently encountered in hematology, may serve as early clinical clues and justify genetic and immunophenotypic assessment. A multidisciplinary approach combining primary care, immunology, hematology, and AI technologies is essential to advance the early detection of IEI. Projects like PIDCAP, and their potential extension to secondary immunodeficiencies, exemplify scalable, patient-centered strategies that may significantly improve diagnostic timeliness and clinical outcomes.

PMID:41550923 | PMC:PMC12808396 | DOI:10.3389/fimmu.2025.1701384

IDCases. 2025 Dec 17;43:e02462. doi: 10.1016/j.idcr.2025.e02462. eCollection 2026.

ABSTRACT

INTRODUCTION: Lophomonas infection is a rare respiratory illness caused by parasites, mostly reported in immunocompromised patients. X-linked agammaglobulinemia (XLA), or Bruton’s disease, is a primary immunodeficiency caused by a defective Bruton’s tyrosine kinase (BTK) gene. This defect results in a deficiency or absence of functional BTK protein, leading to significantly reduced or absent B lymphocytes and serum immunoglobulin levels.

CASE PRESENTATION: A 21-year-old male patient was admitted to our service exhibiting a six-week history of fever, dyspnea, and productive cough. The patient’s condition deteriorated despite prior outpatient management. Following abnormal laboratory values and computed tomography, bronchoscopy was performed. Microscopic evaluation of the bronchoalveolar lavage fluid revealed the presence of viable, oval-shaped, flagellated Lophomonas protozoa.

CONCLUSION: In evaluating immunocompromised patients with sustained respiratory symptoms, clinicians should consider opportunistic infections, such as pulmonary lophomoniasis, in their differential diagnosis. Delayed intervention in this patient population may lead to irreversible adverse sequelae.

PMID:41551350 | PMC:PMC12811521 | DOI:10.1016/j.idcr.2025.e02462

Egypt J Immunol. 2026 Jan;33(1):31-39. doi: 10.55133/eji.330104.

ABSTRACT

Common variable immunodeficiency (CVID) is one of the primary immunodeficiency disorders. The phenotype of peripheral blood memory B cells is a useful tool in the classification of patients into clinically and functionally relevant groups. This study aimed to assess the level of naïve and switched memory B cells level and their correlation with the clinical phenotypes and complications in patients with CVID. This case control study included 30 adult patients with CVID and 30 normal controls, matched for age and sex. Complete blood count, cluster of differentiation 3 (CD3)+, CD4+, CD8+ T cells and CD19+27-IgD+ for naïve B cells and CD19+27+IgD- switched memory B cells levels were assessed. The mean age of the onset of symptoms was 16.9±15.1 years, the mean age of diagnosis was 27.30±14.39 years, with a diagnostic delay of 10.43±10.29 years, and the body mass index was significantly lower in CVID group. Infections including (upper respiratory tract infection, chronic diarrhea, pneumonia and bronchiectasis) were the most frequent phenotypes. CD4+, CD4+/CD8+ T cells, CD19+ and CD19+27+IgD- switch memory B cell, IgG, IgA, and IgM were significantly lower in CVID group than in the control group (p < 0.001 and p < 0.015, respectively). CD8+ T cells and CD19+27-IgD+ naïve B cells were significantly higher in the CVID group (p < 0.001). CD19+27-IgD+ naïve B cells level was significantly lower in cases with bronchiectasis with low baseline serum IgG in lymphadenopathy group (p=0.049), and higher level of CD3+ T cells in cases with splenomegaly. There was no significant difference in laboratory results in CVID patients presented with autoimmune diseases, Granulomas nor enteropathy. In conclusion, high level of CD19+27-IgD+ naïve and low level of CD19+27+IgD- switch memory B cells are characteristic features of CVID. Moreover, the reduced CD19+27-IgD+ naïve B cells level can be a predictor of the development of bronchiectasis in CVID patients.

PMID:41546855 | DOI:10.55133/eji.330104

Mol Ther Nucleic Acids. 2025 Dec 18;37(1):102808. doi: 10.1016/j.omtn.2025.102808. eCollection 2026 Mar 12.

ABSTRACT

Nonsense mutations are among the genetic causes of LRBA (lipopolysaccharide-responsive beige-like anchor) deficiency, a rare autosomal-recessive immunodeficiency disorder. These mutations introduce premature stop codons, leading to the loss of LRBA protein expression. Following the recent market withdrawal of ataluren, the only approved translational readthrough-inducing drug (TRID), there is an urgent need for alternative therapeutic options. In this study, we investigated the efficacy of three 1,2,4-oxadiazole-based TRIDs-NV848, NV914, and NV930-using primary fibroblasts from a patient homozygous for the R1683X nonsense mutation. All compounds restored full-length LRBA protein with correct cytoplasmic localization, as confirmed by western blot and immunofluorescence, outperforming ataluren in readthrough efficiency. NV848 exhibited the strongest activity and uniquely increased LRBA mRNA levels, suggesting transcript stabilization. In contrast, NV930 and NV914 induced readthrough without stabilizing mRNA. Global proteomic profiling revealed minimal off-target effects for NV848, limited protein modulation by NV914, and widespread variations of 828 proteins by NV930, affecting pathways related to vesicular transport and mRNA splicing. However, network analysis revealed poor connectivity among differentially expressed proteins, with LRBA unrelated to any regulated cluster. These findings highlight the reported molecules as promising candidates for precision therapy in LRBA deficiency and shed light on the broader cellular impact of TRIDs.

PMID:41541268 | PMC:PMC12803801 | DOI:10.1016/j.omtn.2025.102808

Front Stroke. 2024 Nov 8;3:1390220. doi: 10.3389/fstro.2024.1390220. eCollection 2024.

ABSTRACT

There is an increasing global burden of pediatric stroke especially in low- and middle-income countries (LMICs). This is worsened by the specific risk factors in these areas, including Sickle Cell Disease and endemic infections like Tuberculosis and Human Immunodeficiency disease. Stroke occurs 221-300 times more frequently in patients with SCD when compared to healthy children. Although established stroke units and acute stroke care can improve outcomes, these are often not available in resource-poor settings. Primary and secondary prevention of strokes become a very important strategy to reduce the mortality and debilitating physical and cognitive long-term effects of stroke. There are myriads of challenges with implementing already established global policies and guidelines for stroke care in LMICs. These include paucity of data on this subject, poor knowledge and awareness about the symptoms of childhood stroke, adverse cultural beliefs regarding strokes, lack of screening and diagnostic equipment, inadequately trained manpower as well as nonexistent evidence-based management guidelines in these regions. To address these challenges, simple, cost-effective, stroke care models that determine the process of care and how available services should be delivered have been proposed to suit the peculiarities of LMICs in the areas of stroke risk assessment, prevention, and management.

PMID:41542266 | PMC:PMC12802630 | DOI:10.3389/fstro.2024.1390220

Nat Immunol. 2026 Jan 15. doi: 10.1038/s41590-025-02381-7. Online ahead of print.

ABSTRACT

The E3 ubiquitin ligase Casitas B-lineage lymphoma (CBL) promotes positive selection and antigen responses in mouse T lymphocytes by ubiquitinating ZAP70. Conversely, mouse CBL and CBL-B mutually redundantly regulate SYK ubiquitination and B cell receptor signaling. Here we studied individuals with somatically homozygous CBL loss-of-function variants in leukocytes. Human CBL is largely redundant for the development and function of human T cells. Conversely, B cell development is altered at the immature stage, with a tenfold increase in transitional cells, enhanced survival of autoreactive clones and impaired tolerance manifested by autoantibody production. B cell maturation is intrinsically impaired by reduced apoptosis and dysregulated B cell receptor signaling. CBL deficiency impairs humoral immunity by limiting memory B cell formation and reducing class switching and somatic hypermutation. Consequently, antigen-specific B cell generation and adaptive immune memory are disrupted, predisposing individuals to infection. Human CBL is critical for B cell development and function but redundant for T cell biology.

PMID:41540267 | DOI:10.1038/s41590-025-02381-7

Stem Cell Res. 2026 Jan 13;91:103912. doi: 10.1016/j.scr.2026.103912. Online ahead of print.

ABSTRACT

CHARGE syndrome is a rare, complex congenital disorder affecting multiple organ systems, with CHD7 identified as its primary causative gene. Individuals with CHARGE syndrome can exhibit T cell immunodeficiency, which compromises adaptive immunity and increases susceptibility to infections. T cell immunodeficiency in CHARGE syndrome is largely attributed to thymic hypo/aplasia. In this study, we generated an induced pluripotent stem cell (iPSC) line from the blood of a 21-month-old female with CHARGE syndrome and athymia who carries a de novo CHD7 pathogenic variant, c.1366C > T (p.Q456*). This iPSC line provides a valuable model for investigating the pathogenesis of CHARGE-associated T cell immunodeficiency.

PMID:41539084 | DOI:10.1016/j.scr.2026.103912

J Pediatr Hematol Oncol. 2026 Jan 14. doi: 10.1097/MPH.0000000000003159. Online ahead of print.

ABSTRACT

The recombination activating gene 1 (RAG1) is essential for V(D)J recombination and lymphocyte development. While biallelic null RAG1 mutations cause severe combined immunodeficiency (SCID), hypomorphic variants have increasingly been associated with immune dysregulation and hematologic malignancies. This study aimed to present a pediatric case of Epstein-Barr virus (EBV)-negative Burkitt lymphoma carrying a novel homozygous RAG1 variant and to discuss its potential association with immune function and malignancy risk. A 9-year-old Turkish male from a consanguineous family was evaluated for hereditary cancer predisposition. Clinical, immunologic, and genetic assessments were performed, including whole-exome sequencing (WES), Sanger validation, and mRNA expression analysis. The patient presented with cervical lymphadenopathy and was diagnosed with EBV-negative Burkitt lymphoma; he had no recurrent infections, abnormal vaccine reactions, or SCID-related features. Immunologic testing, including lymphocyte subsets and immunoglobulin levels, was within normal limits. WES identified a homozygous RAG1 variant (NM_000448.2:c.460C>T; p.Leu154Phe), predicted to be deleterious and absent from population databases. Both the patient and his healthy dizygotic twin were homozygous, while parents were heterozygous carriers. RAG1 mRNA expression was reduced in heterozygotes but similar in homozygous and wild-type individuals; enzymatic activity was not assessed. The patient responded to chemotherapy and remains in remission under follow-up. In conclusion, this case expands the phenotypic spectrum of hypomorphic RAG1 variants to include EBV-negative Burkitt lymphoma without overt immunodeficiency, suggesting a possible link between partial RAG1 dysfunction and pediatric lymphoma susceptibility.

PMID:41538412 | DOI:10.1097/MPH.0000000000003159

Cureus. 2025 Dec 14;17(12):e99208. doi: 10.7759/cureus.99208. eCollection 2025 Dec.

ABSTRACT

Common variable immunodeficiency (CVID) is a primary immunodeficiency that often goes unrecognized until adolescence or adulthood. Granulomatous-lymphocytic interstitial lung disease (GLILD) is a non-infectious pulmonary complication of CVID that can be subtle, sometimes presenting before significant infections or systemic symptoms. A 19-year-old female patient presented with mild flu-like symptoms. Examination revealed splenomegaly, and routine labs showed mild anaemia and thrombocytopenia. Despite rapid recovery from influenza A, persistent splenomegaly prompted further evaluation. Chest CT demonstrated multiple nodules, ground-glass opacities, and mediastinal lymphadenopathy, findings surprisingly disproportionate to her mild symptoms. Her history of recurrent childhood infections, combined with marked hypogammaglobulinemia and abnormal B-cell immunophenotyping (including increased CD21^low B cells), raised suspicion for CVID. Lung biopsy confirmed GLILD. She was started on immunoglobulin replacement therapy, and at follow-up, her pulmonary lesions remained stable with no new infections. This case highlights how CVID can present subtly, with imaging findings that far exceed the apparent clinical severity. GLILD may be the first clue to an underlying immunodeficiency, emphasizing the importance of a detailed history, immunologic testing, and histopathologic confirmation. Timely recognition allows for early initiation of therapy and close monitoring, potentially improving long-term outcomes. Even mild respiratory symptoms may mask serious underlying immune dysregulation. Clinicians should consider primary immunodeficiencies like CVID in young adults when imaging or lab findings are inconsistent with common infections, as early diagnosis can significantly impact management and prognosis.

PMID:41536406 | PMC:PMC12799267 | DOI:10.7759/cureus.99208

Transpl Infect Dis. 2026 Jan 13:e70162. doi: 10.1111/tid.70162. Online ahead of print.

ABSTRACT

BACKGROUND: Herpes simplex virus (HSV) infection is a significant risk in hematopoietic stem cell transplant (HSCT) recipients, and antiviral resistance poses many clinical challenges.

METHODS: A retrospective case series of eight pediatric patients with acyclovir-resistant HSV infection, determined via genotypic sequencing, post allogeneic HSCT between 2012 and 2025.

RESULTS: Indications for HSCT included primary immunodeficiency, sickle cell disease, myelodysplastic syndrome (MDS), and relapsed/refractory leukemia. All patients received acyclovir prophylaxis. TK mutations were most common (n = 7, 87.5%). Infections manifested as mucocutaneous disease, pneumonitis, keratitis, enterocolitis, and blood viremia. A total of 87.5% of patients (n = 7) were treated with second-line antivirals (foscarnet and/or cidofovir), and three patients were treated with third-line antivirals (pritelivir). Treatment was complicated by nephrotoxicity (n = 3, 37.5%). Adjunct treatments included intravenous immunoglobulin (n = 3, 37.5%) and donor lymphocyte infusion (n = 1, 12.5%). Poor outcomes were seen across the cohort, including death (n = 3, 37.5%). T-cell depletion was used in 50% of patients (n = 4). Concomitant immunosuppressive therapy was used in 100% of patients (n = 8) and high-dose steroids were used in 50% of patients (n = 4). Graft versus host disease occurred in four patients (50%). Secondary complications included transplant-associated thrombotic microangiopathy (n = 3, 37.5%), idiopathic pulmonary syndrome (n = 3, 37.5%), and graft failure (n = 1, 12.5%).

CONCLUSION: Acyclovir-resistant HSV infection in pediatric HSCT recipients is associated with high morbidity and mortality, limited therapeutic options, and significant treatment-related nephrotoxicity. Early recognition, early resistance testing, prompt initiation of second-line therapy, and weaning of immunosuppression are critical. Emerging therapies, such as helicase-primase inhibitors and adoptive T-cell therapy, hold promise but remain limited by access and pediatric data.

PMID:41531120 | DOI:10.1111/tid.70162