Research

J Clin Immunol. 2025 Nov 12;45(1):159. doi: 10.1007/s10875-025-01960-5.

ABSTRACT

Haploinsufficiency of cytotoxic T-lymphocyte associated protein 4 (CTLA4), a known cause of inborn errors of immunity, can lead to autoimmunity, inflammation, neoplasia and infections. A previously undescribed CTLA4 variant was identified in a patient who presented with life-threatening cutaneous infection caused by Pseudomonas aeruginosa, severe VZV infection, and Evans syndrome. Our aim was to assess the pathogenicity of the previously undescribed c.379T > G variant in the CTLA4 gene and explore its phenotypic presentation in relatives. We employed genetic and protein-based in silico analyses to evaluate the potential role of the c.379T > G variant in the CTLA4 gene. We subsequently studied CTLA4 expression ex vivo, analyzed the clinical presentation of affected carriers and compared the biological status across affected individuals, healthy carriers and noncarriers. In silico analyses revealed that the c.379T > G mutation, which is located within the ligand binding area of CTLA4, is highly pathogenic. Its clinical manifestations, which are sometimes fatal, include multiple infections, autoimmunity, inflammation of the central nervous system, lymphoproliferation and thymoma with Good’s syndrome. Compared with its expression in healthy donors, the expression of CTLA4 following stimulation in memory regulatory T cells was decreased in affected individuals. Immunophenotyping revealed an increased proportion of immature and double-negative B cells in affected patients compared with their nonmutated relatives. Additionally, a reduction in naive T cells and an increase in CD4 + CD25-Foxp3 + cells were observed in carriers compared with controls. The c.379T > G variant of CTLA4, resulting in a p.Tyr127Asp substitution, is pathogenic and contributes to the development of a CTLA4 haploinsufficiency phenotype. This finding highlights the heterogeneous presentations of the disease, including oncological and neurological manifestations.

PMID:41219619 | DOI:10.1007/s10875-025-01960-5

J Clin Immunol. 2025 Nov 10;45(1):156. doi: 10.1007/s10875-025-01956-1.

ABSTRACT

Combined immunodeficiency due to CARMIL2 mutations is a rare autosomal recessive primary immunodeficiency characterized by impaired T-cell activation and function, leading to diverse clinical manifestations. Fewer than 50 cases have been reported worldwide. We describe the clinical and genetic features of five patients from Palestine with homozygous CARMIL2 mutations, including the first documented case of recurrent visceral leishmaniasis associated with this gene defect. This retrospective case series was conducted using whole-exome sequencing to confirm the diagnosis. All patients exhibited significant immunologic symptoms, including chronic dermatitis, cutaneous warts, recurrent respiratory infections, and mucocutaneous candidiasis. Two developed cytomegalovirus-related disease. Genetic analysis revealed two novel homozygous variants: NM_001317026.3:c.1865 C > T (p.Ala622Val) in four patients, and c.1973 C > T (p.Ala658Val) in one. Notably, one adult male developed recurrent visceral leishmaniasis, an unusual presentation not previously reported in the context of CARMIL2 deficiency. Consanguinity was identified in two families. All patients required immunomodulatory therapy, and four were evaluated for hematopoietic stem cell transplantation. This case series underscores the clinical heterogeneity of CARMIL2-associated immunodeficiency and highlights the importance of genetic testing in patients with recurrent or atypical infections, particularly in populations with a high prevalence of consanguinity. The novel link to visceral leishmaniasis expands the known phenotypic spectrum of this condition.

PMID:41207919 | DOI:10.1007/s10875-025-01956-1

Fish Shellfish Immunol. 2025 Nov 6:110987. doi: 10.1016/j.fsi.2025.110987. Online ahead of print.

ABSTRACT

Triploid fish are considered a promising candidate for aquaculture; however, their immunological properties remain incompletely characterized. In this study, we investigated the immunological differences between 10-month-old triploid and diploid grass carp. Triploids exhibited a higher head kidney index and obvious macrophage aggregation in the head kidney compared to diploids. Among the immune and antioxidant indices, serum IgM content, head kidney lysozyme and acid phosphatase activities, and catalase and total superoxide dismutase activities, were significantly elevated in the triploids. Transcriptomic analysis identified 610 differentially expressed genes (DEGs) in the head kidney between triploids and diploids. KEGG pathway enrichment analysis revealed that these DEGs were primarily associated with primary immunodeficiency and phagosome pathways. Notably, genes involved in antigen presentation, immunoregulation, phagocytosis, and inflammation were significantly down-regulated in triploids. In contrast, MYD88, macrophage proliferation genes, and macrophage marker genes were up-regulated. Further investigation into macrophage function demonstrated that triploid macrophages exhibited reduced phagocytic capacity, but maintained respiratory burst activity comparable to that of diploids. This was accompanied by elevated expression of respiratory burst-related and lysosome-associated genes. Collectively, these findings suggest that although triploid grass carp exhibit diminished macrophage phagocytosis and inflammatory responses, compensatory immune regulatory mechanisms may be at play. This study provides a theoretical foundation for the application of triploid grass carp in aquaculture.

PMID:41205782 | DOI:10.1016/j.fsi.2025.110987

Medicine (Baltimore). 2025 Nov 7;104(45):e45565. doi: 10.1097/MD.0000000000045565.

ABSTRACT

RATIONALE: Extreme elevation of serum immunoglobulin E (IgE) concentration is a key marker for detecting immune disorders, including humoral and cellular defects in primary immunodeficiency (PID). IgE antibodies are present in low concentrations in the body and are produced in large amounts when exposed to infections or toxins. However, IgE is also the cause of allergic symptoms and life-threatening anaphylaxis reactions. Early diagnosis of PID associated with elevated IgE may lead to effective or life-saving therapeutic interventions. Therefore, genomic testing-based diagnosis is becoming a widely used diagnostic tool to determine the cause of disease.

PATIENT CONCERNS: Three Vietnamese patients with increased IgE expression were collected for genetic analysis at The Allergy, Immunology, and Rheumatology Department, Vietnam National Hospital Pediatrics.

DIAGNOSES: Primary immunodeficiency associated with elevated IgE.

INTERVENTIONS: We performed whole-exome sequencing (WES) to detect novel associated variants and confirmed these by Sanger sequencing. The effects of the variants were predicted using in silico prediction tools.

OUTCOMES: Three novel pathogenic variants including c.2204A > T, p.Asp735Val in the PTPRC gene, c.586T > A, p.Phe196Ile in the UNC119 gene, and c.481C > T, p.Arg161Cys in the IL21R gene were found to be associated with increased IgE.

LESSONS: We report novel variants associated with genetic defects that increase IgE found in PID patients. These results emphasize the need for accurate diagnosis and appropriate intervention to improve outcomes and quality of care for individuals with high IgE levels and related immune disorders.

PMID:41204599 | DOI:10.1097/MD.0000000000045565

Clin Immunol. 2025 Nov 5:110637. doi: 10.1016/j.clim.2025.110637. Online ahead of print.

ABSTRACT

Heterozygous pathogenic NFKB1 variants are one of the most frequent monogenic causes of disease in patients with inborn errors of immunity (IEI) and mainly compromise protein expression. NFKB1 encodes the precursor protein p105, which is processed into p50, the key transcription factor of canonical NF-κB1 signaling. Insufficiency of p105/p50 presents with immunodeficiency and autoinflammation. Here, we evaluated two NFKB1 missense variants, identified in compound heterozygosity in cis (c.[150A > C;156A > C]; p.[Gln50His;Lys52Asn]) in a patient with immunodeficiency. While the isomorphic Q50H variant enhanced the rather marginal defect of K52N, the combination of both caused a pathogenic protein damage in p50. Our findings highlight an inherent challenge when analyzing single variants ‘isolated’ from their genetic context. Particularly when filtering out additional variants, e.g. based on allele frequencies, pathogenic effects originating from compound heterozygosity may be overlooked.

PMID:41202999 | DOI:10.1016/j.clim.2025.110637

J Allergy Clin Immunol. 2025 Nov 5:S0091-6749(25)01112-1. doi: 10.1016/j.jaci.2025.10.022. Online ahead of print.

ABSTRACT

BACKGROUND: Immune dysregulation, including autoimmunity, autoinflammation, allergy, and malignancy predisposition, adds significant disease burden in primary immune disorders (PID) and inborn errors of immunity (IEI).

OBJECTIVE: To evaluate whether the 5-graded immune deficiency and dysregulation activity (IDDA2.1) score, encompassing 21 organ involvement and disease burden parameters, supports diagnosis across a wide spectrum of IEI.

PATIENTS AND METHODS: From April 2022 to November 2024, collaborators from 84 centers collected 1,043 IDDA score datasets from 825 patients across 89 IEI (17 disorders with ≥10 patients each; range 1-196/IEI), including 177 scores from 141 treated patients. Supervised machine learning models (k-nearest neighbors, support vector machine, logistic regression, random forest) classified patients into disease groups and ranked corresponding predictive features, while unsupervised UMAP visualized disease-specific clustering.

RESULTS: Feature analysis reflected clinicians’ recognition of IEI patterns and confirmed internal IDDA score consistency. Phenotype profiles in treated patients remained informative, inversely reflecting anticipated treatment-dependent phenotype amelioration. UMAP effectively distinguished IEI by IDDA2.1 profiles. Genetic disorder prediction achieved 73% overall accuracy, 70% for the correct monogenic IEI, and 93% within the top three predictions; classification reached 43% for IEI-IUIS categories and 59% for 12 “cardinal” IEI (25 genes).

CONCLUSIONS: Random Forest Feature importance analysis can inform targeted clinical screening for key disease manifestations. The “top-three” prediction approach demonstrates diagnostic potential, but improved accuracy will require larger, globally shared datasets. Limited sample sizes for rare diseases highlight the necessity of broader collaboration to enhance AI-assisted clinical decision-making in the future.

PMID:41202990 | DOI:10.1016/j.jaci.2025.10.022

Arch Pediatr. 2025 Nov 4:S0929-693X(25)00180-0. doi: 10.1016/j.arcped.2025.07.004. Online ahead of print.

ABSTRACT

In this article, we report the results of four years (2019-2023) of newborn blood spot screening for severe lymphopenia using TREC (T-cell receptor excision circle) quantification in the Pays de la Loire region in France. Our main objective was to analyze underlying causes of T-cell lymphopenia revealed by positive testing. During the study period, 156,892 newborns were screened and ten were identified with T-cell lymphopenia (1/13,260 births), of whom three were diagnosed with severe combined immunodeficiencies (SCID: 1/40,000 births). Our results confirm data from international reports and our previous nationwide study (DEPISTREC; 2015 to 2017). We conclude that routine newborn screening for T-cell lymphopenia is operational to detect and swiftly treat infants with SCID.

PMID:41193336 | DOI:10.1016/j.arcped.2025.07.004

J Med Case Rep. 2025 Nov 5;19(1):567. doi: 10.1186/s13256-025-05649-6.

ABSTRACT

BACKGROUND: This case represents a 2-month old female infant with a rare and challenging case of Omenn syndrome that was the result of a compound heterozygous mutation in recombination-activating gene 2, an occurrence infrequently documented in the literature. The presentation was challenging as the patient complained of recurrent infections and generalized rash. Immunological workup demonstrated preserved T cells and extremely high immunoglobulin E levels. This case highlights the significance of considering leaky severe combined immunodeficiency in the differential diagnosis of early life erythroderma and recurrent infections, despite the absence of typical severe combined immunodeficiency findings.

CASE PRESENTATION: We report the case of a 2-month-old Palestinian Arab female infant, born to nonconsanguineous parents, with a positive family history of immunodeficiency, who presented with persistent high-grade fever, diffuse erythrodermic rash, recurrent lower respiratory tract infections, and failure to thrive. Physical examination revealed generalized lymphadenopathy and hepatosplenomegaly. Initial laboratory investigations showed eosinophilia and markedly elevated serum immunoglobulin E levels. Immunological workup demonstrated profound B-cell lymphopenia, preserved natural killer cell counts, and a cluster of differentiation 4/cluster of differentiation 8 T-cell imbalance. Chest radiography revealed absence of a thymic shadow. Whole exome sequencing identified compound heterozygous mutations in the recombination-activating gene 2, confirming the diagnosis of Omenn syndrome. The patient received aggressive antimicrobial therapy and supportive immunologic care. Despite optimal medical management, she succumbed to infection-related complications at 7 months of age, prior to undergoing hematopoietic stem cell transplantation.

CONCLUSION: This case underscores the diagnostic and therapeutic challenges in managing Omenn Syndrome, particularly in settings where routine newborn screening for severe combined immunodeficiency is not available. Early recognition and genetic diagnosis are vital to initiate life-saving interventions such as hematopoietic stem cell transplantation. Increased awareness among clinicians regarding atypical presentations of primary immunodeficiency can lead to earlier referrals, improved outcomes, and reduction in diagnostic delays.

PMID:41194140 | DOI:10.1186/s13256-025-05649-6

Front Immunol. 2025 Oct 20;16:1638544. doi: 10.3389/fimmu.2025.1638544. eCollection 2025.

ABSTRACT

Inborn errors of immunity (IEI) number more than 500 diseases, with most affected patients being children. Their precise diagnosis is hampered by overlapping phenotypes, and by their ample and varied phenotypic spectrum. We analyzed the contribution of next generation sequencing to the diagnosis of IEI in a cohort of 157 children in a referral hospital in Mexico City. Following the classification of the International Union of Immunological Societies (IUIS), patients were assigned to an IEI group before sequencing, or to an “undefined” group, if it was not possible to assign them to any of them. Patients were again classified in the IUIS groups after sequencing. The diagnostic yield was 32.48%. Before sequencing, the largest group was comprised by patients that could not be assigned to a specific IUIS group (38.35% of the cohort), while after sequencing the largest group was made by the patients where no likely molecular diagnosis was found (67.52% of the cohort). Patients that were assigned to an IUIS group were confirmed to have a disease of that same group in 31.25% of the cases, while in 10.42% the molecular diagnosis corresponded to an immunodeficiency of a different group to the one initially suggested. In 18.03% of the children that could not be assigned to an immunodeficiency group before sequencing, a molecular diagnosis was reached after sequencing. In the patients that remained without a molecular diagnosis, the possibility of new IEI genes was explored by analyzing the variants, first in a curated set of immune related genes, and then across the whole exome. However, after filtering the variants, by frequency, predicted consequence, and known biology, no new IEI candidate genes were identified. This results underscore the large impact of next generation sequencing for the correct diagnosis of IEI, and also points to the need to better understand their genetic architecture in order to increase the diagnostic yield.

PMID:41190063 | PMC:PMC12580210 | DOI:10.3389/fimmu.2025.1638544

Curr Opin Pediatr. 2025 Dec 1;37(6):606-612. doi: 10.1097/MOP.0000000000001513. Epub 2025 Oct 24.

ABSTRACT

PURPOSE OF REVIEW: The purpose of this review is to provide an update on monitoring, prevention, and treatment of infectious and noninfectious complications of phagocytic, humoral, and cellular immune deficiencies.

RECENT FINDINGS: The recognition that immune dysregulatory features are hallmarks of many genetic defects leading to immune deficiency have led to a new name for all congenital disorders that primarily impact immune function – inborn errors of immunity (IEI). While controlling infections is critical for treatment of patients with IEI, recognition and management of noninfectious complications should also be a focus of comprehensive management of these conditions. Major advances in use of definitive therapies including hematopoietic stem cell transplant, gene therapy, and gene editing have allowed for improved outcomes in cellular and phagocytic immune defects.

SUMMARY: There are now over 550 identified IEI, and effective management of these conditions requires a multidisciplinary approach to monitoring, preventing, and treating both infectious and noninfectious complications of IEI.

PMID:41190402 | DOI:10.1097/MOP.0000000000001513