Manish Butte

J Exp Med. 2025 May 5;222(5):e20241432. doi: 10.1084/jem.20241432. Epub 2025 Mar 3.

ABSTRACT

Ataxia telangiectasia and Rad3-related (ATR) kinase and its interacting protein ATRIP orchestrate the replication stress response. Homozygous splice variants in the ATRIP gene, resulting in ATRIP deficiency, were identified in two patients of independent ancestry with microcephaly, primordial dwarfism, and recurrent infections. The c.829+5G>T patient exhibited lymphopenia, poor vaccine responses, autoimmune features with hemolytic anemia, and neutropenia. Immunophenotyping revealed reduced CD16+/CD56dim NK cells and absent naïve T cells, MAIT cells, and iNKT cells. Lymphocytic defects were characterized by TCR oligoclonality, abnormal class switch recombination, and impaired T cell proliferation. ATRIP deficiency resulted in low-grade ATR activation but impaired CHK1 phosphorylation under genotoxic stress. ATRIP-deficient cells inadequately regulated DNA replication, leading to chromosomal instability, compromised cell cycle control, and impaired cell viability. CRISPR-SelectTIME confirmed reduced cell fitness for both variants. This study establishes ATRIP deficiency as a monogenic cause of microcephalic primordial dwarfism, highlights ATRIP’s critical role in protecting immune cells from replication stress, and offers new insights into its canonical functions.

PMID:40029331 | DOI:10.1084/jem.20241432

J Investig Allergol Clin Immunol. 2025 Mar 3:0. doi: 10.18176/jiaci.1059. Online ahead of print.

ABSTRACT

Activated phosphoinositide 3-kinase (PI3K) delta syndrome (APDS) is an ultrarare genetic disorder characterized by overlapping immunodeficiency and immune dysregulation. Its diagnosis poses challenges owing to its clinical similarities with other inborn errors of immunity (IEIs), compounded by the absence of targeted treatments in today’s medical landscape. The standard approach involves symptom management, reducing infection through immunoglobulin replacement therapy and prophylactic antimicrobials, and treating immune dysregulation with immunomodulators. This approach considerably hampers effective management of APDS, as the diverse nature of the disease necessitates a personalized strategy, in which the advantages and risks of immunosuppression are weighed against the potential for recurrent infections and lymphoproliferative complications. To address these challenges, a group of Spanish experts in the management of IEIs, including APDS, collaborated to develop Delphi-based consensus recommendations. The primary goal of the initiative was to offer guidance on various aspects of this complex disease, marking a pioneering effort in Europe. The consensus aims to facilitate early diagnosis and provide clues for individual patient-based decisions that could favor balanced risk-benefit estimations for treatment.

PMID:40028901 | DOI:10.18176/jiaci.1059

Heliyon. 2025 Jan 25;11(4):e42024. doi: 10.1016/j.heliyon.2025.e42024. eCollection 2025 Feb 28.

ABSTRACT

OBJECTIVE: Identifying reliable prognostic markers for breast cancer is crucial for improving survival rates and reducing mortality. Recent studies highlight the AT-rich interactive domain-containing protein (ARID) family, particularly ARID3A, as influential in cancer progression, though its specific role in breast cancer remains unclear. This study investigates ARID3A’s expression, prognostic relevance, clinicopathological correlations, co-expression profiles, and protein-protein interactions in breast cancer.

METHODS: ARID3A mRNA and protein expression levels were analyzed using UALCAN, GEPIA databases, and immunohistochemistry from our hospital samples. Clinical prognostic parameters and survival data were examined through bioinformatics tools, including GEPIA, Bc-GenExMiner, and BEST. Subtype-specific expression and co-expression, particularly with REXO1, were evaluated using LinkedOmics, TIMER, and bc-GenExMiner. Functional enrichment analysis was conducted via LinkedOmics. Protein-protein interactions (PPI) were established using GeneMANIA and STRING, with validation through molecular docking using Cluspro.

RESULTS: Elevated ARID3A expression was associated with poor prognosis in breast cancer, particularly in Luminal and HER2-positive subtypes. A positive correlation with REXO1 was identified, and enrichment analysis emphasized ARID3A’s involvement in immune-related pathways, such as “interferon gamma production” and “primary immunodeficiency.” PPI network and docking studies identified TP53 as a potential binding partner, suggesting a novel interaction influencing tumor progression.

CONCLUSION: These findings indicate that ARID3A may serve as a prognostic biomarker and therapeutic target in breast cancer, providing insights into its involvement in oncogenic pathways and interactions, particularly with TP53, that may drive cancer development and progression.

PMID:40028521 | PMC:PMC11868939 | DOI:10.1016/j.heliyon.2025.e42024

Heliyon. 2025 Feb 4;11(4):e42408. doi: 10.1016/j.heliyon.2025.e42408. eCollection 2025 Feb 28.

ABSTRACT

Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disorder characterized by recurrent infections, severe eczema, and elevated serum immunoglobulin E (IgE) levels. Genetic testing traditionally focuses on known genes such as STAT3 and DOCK8, responsible for the majority of autosomal-dominant (AD-HIES) and autosomal-recessive (AR-HIES) cases, respectively. However, a significant subset of patients with HIES-like symptoms remain genetically unexplained. Whole-exome sequencing (WES) has emerged as a transformative diagnostic tool, enabling the identification of both novel and incidental genetic mutations. This report highlights the role of WES in diagnosis of AD-HIES, showcasing its utility in detecting a STAT3 mutation while revealing a concurrent BRCA2 pathogenic variant. While the STAT3 mutation confirmed the diagnosis of AD-HIES, the incidental BRCA2 finding underscores the importance of genetic counseling and long-term surveillance.

PMID:40028518 | PMC:PMC11870154 | DOI:10.1016/j.heliyon.2025.e42408

Clin Immunol. 2025 Feb 28:110469. doi: 10.1016/j.clim.2025.110469. Online ahead of print.

ABSTRACT

IKAROS, encoded by IKZF1, is a six zinc-finger (ZF) transcription factor integral to lymphocyte development and function. IKZF1 mutations affecting DNA-binding (ZF1-4) and dimerization (ZF5-6) have been extensively reported and result in human disease. Herein, we investigated IKZF1 mutations affecting protein stability. We identified ten individuals in three families carrying IKZF1 mutations mapping either to the pre-ZF1 area (D22N), or the dimerization domain (M494Vfs*86, Y503*) presenting with infections, immune dysregulation and/or lymphoproliferation with incomplete clinical penetrance. IKAROS expression was reduced in all mutation-carrier evaluated. Protein stability was decreased for D22N, V52L (another pre-ZF1 variant reported in COSMIC), Y503* and Del1-116, a laboratory-designed mutant encompassing the pre-ZF1 area. Mutants Y503* and Del1-116 also exhibited other impaired functions. IKAROS N-terminal pre-ZF1 area, encompassing a previously uncharacterized protein stability-associated region (PSAR), is crucial for IKAROS stability. Variants in the IKAROS PSAR leading to decreased protein stability and IKAROS haploinsufficiency seem sufficient to result in immune defects and IKAROS-associated diseases.

PMID:40024461 | DOI:10.1016/j.clim.2025.110469

Lancet Rheumatol. 2025 Feb 27:S2665-9913(24)00348-5. doi: 10.1016/S2665-9913(24)00348-5. Online ahead of print.

ABSTRACT

BACKGROUND: Suppressor of cytokine signalling 1 (SOCS1) insufficiency is an inborn error of immunity affecting the negative regulation of cytokine and growth factor signalling. We aimed to enhance the understanding of clinical manifestations, disease trajectories, disease penetrance, and the effect of Janus kinase (JAK) inhibition in individuals with SOCS1 insufficiency.

METHODS: This study used data from two independent cohorts: the European Society for Immunodeficiencies (ESID) registry and the UK Biobank. Participants from the ESID registry were from nine European countries (Austria, Belgium, France, Germany, Ireland, Italy, Portugal, Sweden, and Ukraine), China, Taiwan, and the USA. Participants from the ESID registry were eligible if they had heterozygous, functionally validated SOCS1 variants; participants from the UK Biobank were included if they had any SOCS1 variant detected in the ESID registry cohort or any other SOCS1 variant that was classed as high-impact. Clinical manifestations of the underlying SOCS1 insufficiency were documented and summarised into nine subgroups, with ICD-10 diagnosis codes collected for participants from the UK Biobank. Participants from the ESID registry were tested for relevant autoantibodies in their local laboratory. Responses to JAK inhibitor treatment in participants from the ESID registry were assessed by the treating physician using a visual analogue scale. Descriptive statistics were used for analysis. People with lived experience were not involved in the study design.

FINDINGS: We included 119 participants with SOCS1 insufficiency: 67 from the ESID registry, enrolled between Feb 15, 2021, and Dec 31, 2023, and 52 from the UK Biobank. Of the 67 participants from the ESID registry, 39 (58%) were female, 28 (42%) were male, and the median age was 28 years (IQR 15-44, range 2-85). 27 different monoallelic SOCS1 variants were identified in these participants. 62 (93%) of the 67 participants in the ESID registry cohort were symptomatic and five (7%) were asymptomatic family members; of the 62 participants with symptoms, allergy (33 [50%]), inflammatory gastrointestinal (22 [36%]) and skin (18 [29%]) manifestations, autoimmune cytopenia (24 [39%]), and lymphoproliferation (23 [37%]) were most frequent. Rheumatological manifestations (23 [37%]) included systemic lupus erythematosus, Sjögren’s disease, and rheumatoid arthritis, with typical autoantibody profiles. 42 (68%) of the 62 symptomatic participants had at least three different manifestations. In the UK Biobank we found 52 participants carrying high-impact SOCS1 variants; 29 (56%) were female, 23 (44%) were male, and the median age was 72 years (65-78, 57-86). Only 30 (58%) of these participants had developed manifestations that were potentially related to SOCS1 insufficiency. Allergy and rheumatological manifestations were more common in participants from the UK Biobank than the ESID registry. Female predominance (21 [70%] of 30 participants were female and nine [30%] were male) was also found among symptomatic participants from the UK Biobank. Treatment with JAK inhibitors showed promising results in 12 (92%) of 13 participants in the ESID registry.

INTERPRETATION: SOCS1 insufficiency differs from other genetic autoimmune lymphoproliferative disorders by the presence of frequent atopic and rheumatological manifestations. Penetrance is incomplete and is higher in females than in males. JAK inhibition is a promising targeted therapy for patients with SOCS1 insufficiency.

FUNDING: German Research Foundation (DFG).

PMID:40024253 | DOI:10.1016/S2665-9913(24)00348-5

Int J Surg Case Rep. 2025 Feb 18;128:111073. doi: 10.1016/j.ijscr.2025.111073. Online ahead of print.

ABSTRACT

INTRODUCTION AND IMPORTANCE: Epstein-Barr virus (EBV) is a common virus infecting more than 90 % of the adult population, typically without symptoms. While most infections remain asymptomatic, EBV is associated with over 200,000 new cancer cases annually. It is linked to several malignancies, including leiomyosarcoma (LS) in immunocompromised patients, a rare occurrence with fewer than 100 new cases per year globally. This report highlights the case of an EBV-associated intracranial leiomyosarcoma in a 4-year-old immunodeficient child.

CASE PRESENTATION: A 4-year-old girl with a history of primary immune deficiency and multiple infections presented with febrile dyspnea. Imaging revealed a right temporo-parietal brain mass, which increased in size over 50 days. Surgical excision was performed, and histological examination showed a tumor with smooth muscle cell characteristics. Immunohistochemical analysis was positive for vimentin and CD99, while EBV genome presence was confirmed by in situ hybridization. The final diagnosis was EBV-associated malignant smooth muscle tumor. The postoperative course was favorable, and chemotherapy was not indicated.

CLINICAL DISCUSSION: Leiomyosarcoma is extremely rare in immunocompetent children but more common in immunocompromised individuals, where EBV infection plays a significant role in tumor development. Although EBV-related leiomyosarcomas occur more frequently in immunodeficient children, intracranial cases are exceptionally rare. These tumors are often challenging to diagnose due to their undifferentiated appearance. The detection of EBV DNA using in situ hybridization is crucial for confirming the diagnosis. While EBV-associated leiomyosarcomas generally respond well to therapy, the optimal treatment remains unclear, with surgery and radiotherapy being the primary approaches.

CONCLUSION: EBV-associated smooth muscle tumors are rare but increasing in incidence among immunocompromised patients. Early recognition of EBV infection in smooth muscle tumors, especially in children with immune deficiencies, is vital for diagnosis. Histological and molecular examination, including in situ hybridization, is essential to confirm the presence of EBV. Treatment typically involves complete surgical excision, with chemotherapy’s role still uncertain.

PMID:40024176 | DOI:10.1016/j.ijscr.2025.111073

J Allergy Clin Immunol Pract. 2025 Feb 27:S2213-2198(25)00198-9. doi: 10.1016/j.jaip.2025.02.026. Online ahead of print.

ABSTRACT

Chronic norovirus infection can lead to significant diarrhoea, malabsorption, and weight loss in immunodeficiency. The clinical and histological picture in these patients is remarkably similar, suggesting that the virus is a main driver for the enteropathy.

PMID:40023369 | DOI:10.1016/j.jaip.2025.02.026

Anal Chim Acta. 2025 Apr 1;1345:343686. doi: 10.1016/j.aca.2025.343686. Epub 2025 Jan 31.

ABSTRACT

BACKGROUND: UDG (Uracil-DNA glycosylase) is a pivotal enzyme in the base excision repair (BER) mechanism, and it is widely distributed across most organisms. Its primary function is to identify and excise uracil bases from DNA, thereby facilitating the repair of DNA and the creation of apurinic/apyrimidinic (AP) sites. Furthermore, abnormal expression or dysregulation of UDG activity has been closely associated with ageing, cancer, and other diseases such as immunodeficiency and lymphoma. Consequently, the detection of UDG activity is critical for clinical diagnostics. However, there is currently a deficiency in simple and sensitive methods for UDG detection.

RESULTS: To overcome this limitation,a one-step strategy for the sensitive detection of UDG activity was devised, combining nicking enzyme-assisted amplification (NEAA), APE1, and triggered reporter. Following treatment with UDG, the detection probe initiates NEAA, which amplifies a substantial quantity of single-stranded DNA (ssDNA) that is complementary to the triggered reporter. In the presence of APE1 and the amplified triggered probes, the triggered reporter is subjected to continuous cleavage, leading to an enhanced fluorescent signal output. The approach permits more convenient and sensitive UDG detection, with a detection limit of 1 × 10ˆ-5 U/mL and a linear range from 1 × 10ˆ-3 to 1 × 10ˆ-5 U/mL.

SIGNIFICANCE: The biosensor described in this strategy detects UDG activity as a one-pot simple reaction without cumbersome assay steps. And it has excellent detection limit and linear range in the detection of biological samples. It will provide a simple and fast solution in the field of UDG activity detection.

PMID:40015794 | DOI:10.1016/j.aca.2025.343686

J Exp Med. 2025 Apr 7;222(4):e20242179. doi: 10.1084/jem.20242179. Epub 2025 Feb 27.

ABSTRACT

COPA syndrome, an autosomal-dominant inborn error of immunity, is nonpenetrant in ∼20% of individuals, with no known mediators of protection. Recent studies implicate STING in the pathogenesis of COPA syndrome. We show that the common HAQ STING allele mediates complete clinical protection. We sequenced 35 individuals with COPA mutations, 26 affected patients and 9 unaffected carriers, finding HAQ STING co-segregation with clinical nonpenetrance. Exome sequencing identified only the mutations comprising HAQ STING as variants shared by unaffected carriers and absent in patients. Experimentally, we found that HAQ STING acts dominantly to dampen COPA-dependent STING signaling. Expressing HAQ STING in patient cells rescued the molecular phenotype of COPA syndrome. Our study is the first report of a common and well-tolerated allele mediating complete clinical protection from a severe genetic disorder. Our findings redefine the diagnostic criteria for COPA syndrome, expose functional differences among STING alleles with broad scientific and clinical implications, and reveal a potential universal gene therapy approach for patients.

PMID:40014299 | DOI:10.1084/jem.20242179