Manish Butte

Front Immunol. 2025 Oct 7;16:1675097. doi: 10.3389/fimmu.2025.1675097. eCollection 2025.

ABSTRACT

BACKGROUND: Major histocompatibility complex (MHC) Class I deficiency is a rare form of primary immunodeficiency that typically presents with recurrent sinopulmonary infections, bronchiectasis, and granulomatous skin lesions during late childhood or adolescence.

METHODS: This retrospective study describes the clinical, immunological, and long-term follow-up data of 11 patients diagnosed MHC Class I deficiency.

RESULTS: The cohort included 11 patients (6 males, 5 females) with a median age of 26 years (range 19-44). The median age at diagnosis was 19 years, with a diagnostic delay of 14 years. Bronchiectasis was seen in 10 patients, granulomatous skin lesions in 6, uveitis in 5, and nasal septum perforation in 3. All but one patient survived during a median follow-up of 11 years. HLA-ABC expression ranged from 0% to 73%, with persistently low mean fluorescence intensity (0.4-3.8). IgM levels were reduced in 7 patients. Ten patients were persistently positive for anti-rubella IgM, including all six with granulomatous skin lesions. Immunophenotyping revealed reduced CD3⁺ (n=2), CD4⁺ (n=3), CD8⁺ (n=3), CD19⁺ (n=5), CD3^–CD16⁺CD56⁺ (n=3), CD19+ IgM-27+ IgD- (switched memory B cells) (n=7), and CD19+ IgM-27+ IgD+ (marginal zone B cells) (n=8). All patients had elevated γδ+ T cells, and NK cells were reduced in three. Seven patients had TAP1 and four had TAP2 mutations, with no significant genotype-phenotype differences.

CONCLUSION: MHC Class I deficiency presents a broad clinical spectrum from asymptomatic to life-threatening disease. Granulomatous tissue damage and uveitis contributed to morbidity. Persistent rubella-specific IgM in most patients, including those without granulomas, is a novel serologic finding that may reflect altered antiviral immunity. Its clinical significance remains uncertain and, further studies with tissue-based viral detection are needed to clarify this observation.

PMID:41126834 | PMC:PMC12537883 | DOI:10.3389/fimmu.2025.1675097

Nat Commun. 2025 Oct 21;16(1):9312. doi: 10.1038/s41467-025-64360-8.

ABSTRACT

The maintenance of metabolic homeostasis relies on the ability to flexibly transit between catabolic and anabolic states in response to insulin signaling. Here we show insulin-activated ATM is a critical mediator of this process, facilitating the swift transition between catabolic-and-anabolic fates of glucose by regulating the functional status of PKM2 and HIF1α. In Ataxia-Telangiectasia (A-T), these mechanisms are disrupted, resulting in intrinsic insulin resistance and glucose intolerance. Consequently, cells exhibit a compensatory dependence on glutamine as an alternative metabolite for energy metabolism. Cerebellar degeneration, a hallmark of A-T, is characterized by the pronounced vulnerability of Purkinje cells, attributed to their unexpected sensitivity to insulin. Supplementation with α-ketoglutarate, the α-keto acid backbone of glutamine, has demonstrated potentials in alleviating glutamine dependence and attenuating Purkinje cell degeneration. These findings suggest that peripheral metabolic deficiencies may contribute to sustained neurodegenerative changes in A-T, underscoring the importance of screening, monitoring and addressing these metabolic disruptions in patients.

PMID:41120320 | DOI:10.1038/s41467-025-64360-8

Blood Adv. 2025 Oct 21:bloodadvances.2025017309. doi: 10.1182/bloodadvances.2025017309. Online ahead of print.

ABSTRACT

Autoimmune hemolytic anemia (AIHA) with an isolated C3d-positive direct antiglobulin test is a rare and understudied condition in children. It typically encompasses cold agglutinin syndrome and paroxysmal cold hemoglobinuria, both transient, infection-triggered disorders collectively referred to as cold AIHA. We report a national cohort of 142 pediatric patients with isolated C3d-positive AIHA, representing 21.6% of all childhood AIHA cases enrolled in the French OBS’CEREVANCE cohort over a 32-year period. The median age at diagnosis was 3.2 years (male-to-female ratio: 1.3), and median follow-up was 2.8 years. Infectious symptoms were present in 63.4% of cases. At diagnosis, median hemoglobin was 6.4 g/dL; 69.7% of patients had inadequate reticulocytosis (BMRI < 121), and 90.4% required transfusions. Eighteen patients (12.7%) had or developed immunopathological manifestations (IM) including five diagnosed with primary immunodeficiency (four with ALPS). Among eight (5.6%) relapsing patients, six had no IM at diagnosis, but four developed IM at relapse. Nine patients were ANA-positive; none progressed to systemic lupus over a median follow-up of 4.9 years. Corticosteroids were administered to 82.4% of patients (median duration: 4.5 months), with no clear benefit over untreated patients regarding hospital stay or transfusion needs. No deaths were reported. In conclusion, pediatric isolated C3d-positive AIHA generally follows a favorable course. However, a minority of patients may reveal underlying immune disorders, highlighting the importance of tailored evaluation at diagnosis. Cold agglutinin testing with thermal amplitude and Donath-Landsteiner testing, rarely performed in this cohort, warrant further study for their impact on diagnosis and clinical management.

PMID:41118608 | DOI:10.1182/bloodadvances.2025017309

Eur J Immunol. 2025 Oct;55(10):e70057. doi: 10.1002/eji.70057.

ABSTRACT

Primary immunodeficiency diseases (PIDs) are inherited disorders caused by genetic defects affecting immune function, leading to recurrent infections, autoimmunity, and malignancies. Many PIDs remain genetically uncharacterized, largely due to rare variants with unclear pathogenicity, which complicates the process of establishing an accurate diagnosis. Next-generation sequencing (NGS) technology enables the identification of molecular defects, improving the diagnosis of PIDs. Functional validation of genetic variants identified through PID-related gene screenings is crucial for determining their clinical significance. In this study, we identified five novel variants in PID-related genes in six families using whole-exome sequencing. These variants include FCHO1 (E44K), NCF2 (A206P), NCF2 (c.174 + 1G > A), STAT1 (L199F), and a copy number deletion in LRBA (exon 9-17). Functional validation was performed for four of these variants: STAT1 (L199F) using pSTAT1 assay, NCF2 (A206P and c.174 + 1G > A) by DHR assay, and FCHO1 (E44K) using CRISPR-mediated genome editing. Overall, the present study expands the knowledge of previously unreported variants in primary immunodeficiency.

PMID:41116289 | DOI:10.1002/eji.70057

J Interferon Cytokine Res. 2025 Oct 20. doi: 10.1177/10799907251389756. Online ahead of print.

ABSTRACT

Signal transducer and activator of transcription 1 (STAT1) mutations are associated with diverse pathologies. Loss-of-function (LOF) heterozygous mutations impair interferon (IFN) signaling, predisposing to Mendelian susceptibility to mycobacterial diseases (MSMDs). This study characterizes a novel STAT1 LOF mutation in a patient with multisystem manifestations. A patient presenting with mycobacterial infection, skeletal abnormalities, and systemic inflammation underwent whole-exome sequencing. The identified STAT1 variant was analyzed via computational tools (PolyPhen-2/SIFT). Molecular biological validation included IFN-α/γ-induced STAT1 phosphorylation assays and fluorescence microscopy for subcellular localization. Clinical features included mycobacterial osteomyelitis, severe rash, dwarfism, hepatosplenomegaly, and elevated inflammatory markers (C-reactive protein/erythrocyte sedimentation rate). A heterozygous STAT1 mutation (NM_007315.4:c.2120T>C; p.Ile707Thr) was identified and predicted as pathogenic. Mutant cells showed reduced STAT1 phosphorylation (64% versus wild-type, P < 0.05) and impaired nuclear translocation post-IFN-α/γ stimulation. Antibiotic therapy achieved clinical resolution without complications. These findings indicated that the STAT1 I707T mutation disrupts IFN-α/γ immunity, expanding the MSMD genotypic spectrum. Genetic screening for STAT1 defects is critical in patients with mycobacterial infections involving skin. Molecular biological studies corroborate mutation pathogenicity, guiding therapeutic decisions.

PMID:41115717 | DOI:10.1177/10799907251389756

J Clin Immunol. 2025 Oct 20;45(1):146. doi: 10.1007/s10875-025-01942-7.

NO ABSTRACT

PMID:41114900 | DOI:10.1007/s10875-025-01942-7

Front Immunol. 2025 Oct 3;16:1646761. doi: 10.3389/fimmu.2025.1646761. eCollection 2025.

ABSTRACT

BACKGROUND: The transcription factors signal transducer and activator of transcription 1 and 3 (STAT1 and STAT3) play essential roles in immune and non-immune cell function. The clinical characterization of patients carrying germline gain or loss-of-function (GOF or LOF) mutations in these genes has significantly improved our understanding of their physiological and pathological roles. Although patients with STAT3 LOF, STAT3 GOF, and STAT1 GOF mutations are classified into distinct inborn errors of immunity (IEI) categories, namely Hyper-IgE Syndrome, Regulatory T cell defects, and predisposition to Mucocutaneous Candidiasis, respectively, there is notable clinical overlap among these disorders.

CASE SUMMARY: We describe a 17-year-old girl with recurrent lung infection leading to bronchiectasis, chronic onychomycosis, recurrent vulvovaginal candidiasis, and oral thrush. Additional findings included short stature, delayed puberty, and retained primary teeth. Laboratory results revealed eosinophilia and elevated IgE serum levels, with a NIH HIES score of 53. A rare heterozygous deletion within the 3’UTR of the STAT3 gene (c.*351_*353del) was identified through a candidate gene approach. Although the variant is in a non-coding region, increased STAT3 phosphorylation and elevated suppressor of cytokine signaling 3 (SOCS3) expressions suggested a potential GOF effect. In silico analysis further predicted that the deletion disrupts microRNA (miRNA) binding sites and RNA binding proteins (RBP), potentially impairing post-transcriptional regulation and contributing to STAT3 overexpression. Given the complexity of the phenotype and the atypical location of the STAT3 variation, whole-exome sequencing (WES) was performed, revealing a heterozygous missense mutation in the STAT1 DNA-binding domain (c.1053G>T, p.L351F), previously reported in autosomal dominant chronic mucocutaneous candidiasis (AD-CMC). Functional assays on lymphocytes confirmed an increased STAT1 phosphorylation compared to both STAT1 LOF patient and healthy controls.

CONCLUSION: This case highlights the diagnostic complexity of overlapping IEI phenotypes and the value of combining targeted and WES strategies. This dual molecular diagnosis, comprising a regulatory variant in STAT3 and a pathogenic coding mutation in STAT1, emphasizes the need to include non-coding regions in genetic analyses. It also underscores the value of using techniques that offer a broader genomic view and capture all coding exons, enabling a more comprehensive correlation with the clinical and immunological phenotype.

PMID:41112238 | PMC:PMC12531231 | DOI:10.3389/fimmu.2025.1646761

Front Immunol. 2025 Oct 2;16:1639318. doi: 10.3389/fimmu.2025.1639318. eCollection 2025.

ABSTRACT

BACKGROUND: Adenosine deaminase 2 deficiency (DADA-2) is an autoinflammatory syndrome caused by mutations in the ADA2 gene. ADA-2 functions as an enzyme in purine metabolism and is presumed to play roles in immune regulation. The clinical spectrum of DADA2varies widely, from vascular inflammation and immune dysregulation to hematological abnormalities, including pure red cell aplasia and hemophagocytic lymphohistiocytosis (HLH). This study aimed to describe the clinical, demographic, and immunological profiles of seven DADA-2 patients to broaden the understanding of its hematological and immunological manifestations and provide insight for early diagnosis and treatment strategies.

METHODS: Data were collected from patient medical records at the Department of Pediatric Allergy and Clinical Immunology, Basaksehir Cam and Sakura City Hospital. The study included genetic analysis, flow cytometry for lymphocyte subpopulations, and ADA-2 enzyme activity measurement.

RESULTS: Seven patients from five families were included, predominantly male, with an average symptom onset at 15 months. Hematological findings were present in all patients, with neutropenia observed at the initial presentation (100%). HLH developed in two patients, contributing to a higher mortality rate of 42.8%. Bone marrow analysis in affected patients revealed hypocellularity and marked T-cell infiltration, with fibrosis detected in one. Despite no evidence of viral triggers (EBV, CMV, VZV, Parvovirus B19), HLH occurred in two patients, suggesting a primary immune dysregulation. Inflammatory and immunodeficiency-related findings were also observed, suggesting a mixed phenotype as the most common presentation. Genotype-phenotype analysis showed that patients with undetectable ADA2 enzyme activity or loss-of-function mutations had more severe hematological involvement. In contrast, a patient with residual enzyme activity exhibited a mixed phenotype. Three patients underwent successful hematopoietic stem cell transplantation (HSCT), reversing disease manifestations.

CONCLUSION: Our findings reinforce that DADA2 can initially present as isolated neutropenia, and frequently exhibits a mixed phenotype encompassing hematologic, immunologic, and inflammatory features. HLH is a severe complication that may arise without infectious triggers. Genetic testing for ADA2 should be incorporated into diagnostic panels for congenital neutropenia to avoid delays in diagnosis. Genotype-phenotype correlations offer some prognostic insights, but residual enzyme activity may not fully predict disease severity, underscoring the need for individualized management.

PMID:41112235 | PMC:PMC12528187 | DOI:10.3389/fimmu.2025.1639318

Clin Rev Allergy Immunol. 2025 Oct 17;68(1):92. doi: 10.1007/s12016-025-09103-9.

ABSTRACT

Immunodeficiencies in adults are increasingly recognized yet often remain underdiagnosed, leading to significant morbidity from recurrent infections, autoimmunity, and malignancy. Both primary immunodeficiencies (PIDs), now known as inborn errors of immunity (IEI), and secondary immunodeficiencies (SIDs) contribute to immune dysfunction in adults. Although SIDs are more common in adults due to factors like medications, malignancies, metabolic disorders, chronic conditions, and protein-losing conditions, IEI-particularly common variable immunodeficiency (CVID)-can also manifest in adulthood with diverse clinical features. Early recognition is crucial, with key warning signs including recurrent sinopulmonary infections, unexplained autoimmunity, poor vaccine responses, chronic diarrhea, bronchiectasis, and persistent lymphadenopathy. The diagnostic approach should be systematic. It begins with a detailed patient history and status followed by the evaluation of immunoglobulin levels, lymphocyte subsets, vaccine-specific antibody responses, and exclusion of secondary causes. Genetic testing, increasingly accessible, plays an important role in confirming the diagnosis of IEI and guiding prognosis and treatment. Management strategies focus on treating the underlying condition in SIDs. Preventive measures, including antimicrobial prophylaxis, vaccination, and immunoglobulin replacement therapy (IGRT) in patients with significant antibody deficiencies, are essential for reducing infections and complications in high-risk patients. Given the growing recognition of adult-onset immunodeficiency, clinicians should maintain a high index of suspicion and adopt a structured diagnostic and management approach to improve patient outcomes and quality of life.

PMID:41107625 | DOI:10.1007/s12016-025-09103-9

Transplant Cell Ther. 2025 Oct 15:S2666-6367(25)01518-0. doi: 10.1016/j.jtct.2025.10.015. Online ahead of print.

ABSTRACT

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is increasingly used in inborn errors of immunity (IEI). A specific spectrum of disease complications at HSCT affect post-HSCT survival in IEI; however, the risk factors for HSCT are poorly studied.

OBJECTIVE: To determine the risk factors for HSCT in IEI.

METHODS: In the current study were included 312 patients with various IEI who received a first allogeneic HSCT in our center from 2012 to 2020. Different approaches to HSCT were used. An association of overall survival (OS) and risk factors, such as active infection (n=73), autoimmunity or inflammation (n=89), malignancy (n=15), unknown genetic diagnosis (n=247), nutritional status determined on body mass index (undernutrition, n=31, obesity, n=25), age at HSCT (>12 years, n=37) and organ damage (n=92) were studied.

RESULTS: Median follow-up after HSCT was 5,2 years (range 1,8-10,5). OS was 74% (95% CI 69-79%). The OS was significantly lower in SCID (n=43) than other IEI (n=269): 49 (95% CI 34-64%) versus 78% (95% CI 73-83%), р<0,0001. The only factor, not affecting survival in IEI was unknown genetic defect, while other factors decreased survival. OS was 43% in active infection (p<0,0001), 61% in autoimmunity or inflammation (p=0,003), 67% in malignancy (p=0,47), 52% in undernutrition and 64% in obesity, (p=0,002), 61% in >12 years old (excluding SCID, p=0,02) and 59% in pre-existing organ damage (p<0,0001).

CONCLUSION: The current study showed several important risk factors for HSCT in IEI. New tools are needed to predict post-HSCT survival in pediatric IEI.

PMID:41106779 | DOI:10.1016/j.jtct.2025.10.015