Manish Butte

Front Immunol. 2025 Feb 28;16:1545630. doi: 10.3389/fimmu.2025.1545630. eCollection 2025.

ABSTRACT

DNA Ligase 4 is critical to nonhomologous end joining, necessary for V(D)J recombination in T and B cell development. Ligase 4 deficiency is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA Ligase 4 gene, that can lead to a wide range of phenotypes. We describe a case of Ligase 4 deficiency causing a type of T-B-NK+ atypical SCID, highlighting the clinical and immunologic manifestations. An eight-year-old female, from São Nicolau Island (Cape Verde), presented at our hospital with a history of recurrent pneumonia and suppurative otitis, multiple skin lesions attributed to fungal and bacterial infections since the age of two, and recurrent diarrhea and growth impairment, beginning at the age of four. The laboratory workup showed almost absent B cells, marked hypogammaglobulinemia, and an impaired response to protein antigens. Flow cytometry revealed normal NK and T cell counts, but with nearly absent naïve T cells and TCR-Va7 expressing T lymphocytes, and reduced proliferative responses to mitogens and antigens. An oligoclonal Vβ repertoire was identified by FACS, and PROMIDISa analysis revealed a skewed TCRa repertoire signature. A 477 PID-related genes NGS panel identified a homozygous R278H mutation in the DNA Ligase 4 gene, previously reported to cause Ligase 4 deficiency. Immunoglobulin replacement and prophylactic therapies were started while waiting for hematopoietic stem cell transplantation. She has experienced fluctuating transaminase levels. The cutaneous biopsy was suggestive of lupus pernio. She has shown recurrent inflammatory signs in her limbs, with documented tenosynovitis on ultrasound. Homozygous R278H in Ligase 4 has been linked to various ranges of manifestations in Ligase 4 deficient patients. In our report, this genotype resulted in T-B-NK+ atypical SCID, that after proper prophylaxis has a predominant autoimmune phenotype.

PMID:40093007 | PMC:PMC11906410 | DOI:10.3389/fimmu.2025.1545630

J Allergy Clin Immunol. 2025 Mar 14:S0091-6749(25)00275-1. doi: 10.1016/j.jaci.2025.02.038. Online ahead of print.

ABSTRACT

BACKGROUND: Interferon regulatory factor-2 binding protein-2 (IRF2BP2) is a transcription factor that plays an important role in regulating immune pathways, angiogenesis, apoptosis, and cell differentiation. Defects in this gene have been implicated in immunodeficiency.

OBJECTIVE: To deepen the understanding of the clinical implications of IRF2BP2 variants, we sought to clinically characterize and functionally test thirty-four individuals with IRF2BP2 variants.

METHODS: We collected 34 subjects across 18 families with mutations in IRF2BP2. Records were abstracted for clinical phenotypes. Functional testing was performed on peripheral blood mononuclear cells (PBMCs). Nuclear factor of activated T cells (NFAT) luciferase gene reporter constructs and quantitative cDNA determinations were used to evaluate repressor activity associated with ectopic expression of various IRF2BP2 mutant constructs in Jurkat cells.

RESULTS: Most subjects had immunodeficiency (91%, n = 30/33) with variable gastrointestinal (65%, n= 20/31) and inflammatory or autoimmune features (57%, n=17/30), including chronic abdominal pain, colitis, diarrhea, constipation, vitiligo, alopecia, and migratory rashes. There was a reduced frequency of memory B-cells with poor immunoglobulin production and reduced calcium flux in response to B-cell receptor stimuli. PBMCs had increased apoptosis in vitro compared to healthy controls. Impaired IRF2BP2 repression of NFAT activation was observed using patient-derived mutant IRF2BP2 constructs compared to wild-type. Similarly, TNF-α transcript levels were higher using patient-derived mutations compared to wild-type IRF2BP2 constructs.

CONCLUSIONS: IRF2BP2 deficiency causes a complex immunodeficiency including gastrointestinal and inflammatory disorders as well as impaired B-cell maturation. Impaired repression of the NFAT pathway appears to enhance proinflammatory signaling through proinflammatory cytokine expression.

PMID:40090425 | DOI:10.1016/j.jaci.2025.02.038

J Allergy Clin Immunol Pract. 2025 Mar 14:S2213-2198(25)00203-X. doi: 10.1016/j.jaip.2025.02.030. Online ahead of print.

NO ABSTRACT

PMID:40088224 | DOI:10.1016/j.jaip.2025.02.030

J Clin Immunol. 2025 Mar 14;45(1):81. doi: 10.1007/s10875-025-01862-6.

ABSTRACT

PURPOSE: To investigate the efficacy, safety, tolerability, and serum IgG trough levels of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% in US pediatric patients with primary immunodeficiency diseases (PIDDs).

METHODS: This phase 3, open-label, prospective study (NCT03277313) was conducted at 17 US centers. Eligible patients aged 2 to < 16 years had PIDDs and had received immunoglobulin G (IgG) at a consistent dose for ≥ 3 months before screening. Participants received fSCIG 10% via dose ramp-up for up to 6 weeks (Epoch 1), then every 3-4 weeks for ≤ 3 years (Epoch 2). The primary endpoint was the rate of acute serious bacterial infections (ASBIs).

RESULTS: Data were provided by 44 participants for Epoch 1 (mean ± SD age: 9.0 ± 3.6 years) and 43 (97.7%) for Epoch 2; 34 (77.3%) completed the study. Two ASBIs (both bacterial pneumonia) were reported in one participant with specific antibody deficiency. The mean rate of ASBIs was 0.04 events/participant-year (99% upper confidence interval limit: 0.20), significantly lower than the regulatory-defined threshold of 1.0 (p < 0.001). The mean rate of all infections was 3.12 events/participant-year. Stable mean serum IgG trough levels were maintained during Epoch 2 (10.4, 9.2, and 9.2 g/L at Months 0, 6, and 12, respectively). Most related treatment-emergent adverse events were mild or moderate in severity. No participant developed anti-recombinant human hyaluronidase neutralizing antibodies; 1/44 participants (2.3%) developed binding antibodies.

CONCLUSION: fSCIG 10% effectively prevented ASBIs in pediatric patients with PIDDs, with a favorable safety profile consistent with previous clinical studies.

PMID:40085358 | DOI:10.1007/s10875-025-01862-6

Oral Health Prev Dent. 2025 Mar 14;23:173-182. doi: 10.3290/j.ohpd.c_1907.

ABSTRACT

PURPOSE: To evaluate hereditary angioedema (HAE) attack frequency associated with dental procedures, determine whether patients with post-dental procedural attacks receive more appropriate treatment after their condition is diagnosed, and investigate the potential impact of perceived risk on patients seeking dental care and dental professionals providing it.

MATERIALS AND METHODS: The observational study included all the eligible adults from the Romanian Hereditary Angioedema Registry who provided informed consent. The impact of dental procedures on the HAE attacks was measured using a structured questionnaire including 20 questions administered via telephone.

RESULTS: Patients experienced dental procedure-related symptoms suggestive of HAE both before (47.6%) and after their condition was diagnosed (51.9%). Before the HAE diagnosis, 86.2% of the patients received glucocorticoids and antihistamines for post-procedural swelling. After diagnosis, 85.3% of the patients were given Icatibant and C1-INH. More than half (55.3%) of the patients reported not seeking dental interventions because of fear of HAE attacks or anticipation of refusal, and 24.7% of them declared they had been denied dental care by dental health professionals at least once.

CONCLUSION: Swelling related to dental procedures was common among the studied HAE patients. Unwarranted medications used before HAE diagnosis for dental post-procedural symptoms were replaced by adequate HAE-specific medications in most patients with established HAE diagnosis. A statistically significant proportion of patients refrained from undergoing dental interventions, and some of them were refused dental care by oral health professionals due to fear of HAE attacks.

PMID:40084797 | DOI:10.3290/j.ohpd.c_1907

Crit Rev Ther Drug Carrier Syst. 2025;42(3):55-88. doi: 10.1615/CritRevTherDrugCarrierSyst.2025044498.

ABSTRACT

Cervical cancer is the fourth most common cause of morbidity and mortality in women. The major causative factor for cervical cancer is primary prolonged infection with human papillomavirus, along with secondary factors such as immunodeficiency, smoking, low socioeconomic standards, poor hygiene, and overuse of oral contraceptives. A grave need exists to practice novel strategies to overcome existing drawbacks of conventional therapy such as chemotherapy, radiation therapy, and surgery. Cancer immunotherapy works by strengthening the immune system of the host to combat against the cancerous cells. Immunotherapy in cervical cancer treatment has demonstrated long-lasting effects; however, the response to such therapies was nominal due to its prominent limitations such as immunosuppressive behavior of the tumor. Presently plethora of nanoplatforms such as polymeric nanoparticles, micelles, liposomes, and dendrimers are being maneuvered with cancer immunotherapy. The amalgamation of nanotechnology and immunotherapy in the treatment of cervical cancer is conceivable due to the mutual association between the tumor microenvironment and immunosurveillance. Safety concerns of nanoplatforms with immunotherapeutics such as toxicity, inflammation, and unwanted accumulation in tissues could be surmounted by surface modification methods. This review highlights the benefits of the amalgamation of nanotechnology and immunotherapy to improve shortcomings applicable to the conventional delivery of cancer treatment. We also aim to outline the nanoimmunotherapy sophistications and future translational avenues in this rapidly flourishing cancer treatment modality.

PMID:40084517 | DOI:10.1615/CritRevTherDrugCarrierSyst.2025044498

Curr Allergy Asthma Rep. 2025 Mar 14;25(1):17. doi: 10.1007/s11882-025-01196-8.

ABSTRACT

PURPOSE OF REVIEW: It seeks to answer key questions about the molecular and cellular mechanisms underlying Hyper IgE Syndrome (HIES), the genetic mutations responsible, and their contributions to both immunodeficiency and allergic manifestations. Additionally, it aims to explore diagnostic strategies and therapeutic approaches that address these overlapping domains, thereby improving disease management.

RECENT FINDINGS: Recent research has identified several pivotal genetic mutations, including those in STAT3, DOCK8, and PGM3, which play critical roles in disrupting immune pathways such as Th17 differentiation and IgE regulation. These molecular defects have been linked to the hallmark features of HIES, including recurrent infections and elevated serum IgE levels, as well as its overlap with atopic conditions like eczema, asthma, and food allergies. Advances in diagnostic tools, such as biomarker identification and genetic testing, have improved the differentiation of HIES from more common atopic disorders. Therapeutic advancements, including the use of targeted biologics and interventions addressing both immunodeficiency and allergic symptoms, have shown promise in enhancing patient outcomes. This review highlights the role of specific genetic mutations in shaping the clinical and immunological phenotype of HIES. Key takeaways include the necessity of integrating molecular insights with clinical observations for accurate diagnosis and the potential of emerging targeted therapies to address both immunological and allergic aspects of the syndrome.

PMID:40082265 | DOI:10.1007/s11882-025-01196-8

Eur J Immunol. 2025 Mar;55(3):e202451433. doi: 10.1002/eji.202451433.

ABSTRACT

Common variable immunodeficiency (CVID) represents an “umbrella” diagnosis due to its clinical and immunological heterogeneity. The primary objective of this study was to describe a cohort of CVID pediatric subjects from clinical, immunological, and genetic viewpoints. Secondary, we propose a model for prioritizing genetic investigations in these patients. Thirty-four patients with CVID followed at Meyer Children’s Hospital, IRCSS, were enrolled. Whole exome sequencing was performed according to the latest International Union of Immunological Societies 2022 update. Genetic variants were identified in 16 patients (47%), including known variants in SLC39A7, PRKCD, STAT3, NFKB1, PIK3R1, PLCG2, RFXANK, PRKDC, TNFRSF13B, and novel variants in SPI1, NFKB1, NFKB2. Comparing the Gene+ and Gene- cohorts, we demonstrated that a monogenic cause is more likely to be found in cases of early disease onset, positive family history, autoimmunity, lymphoproliferation, and specific immunological alterations. Using these criteria, we developed a pediatric monogenic CVID (Mo-CVID) score to hypothesize when a CVID pediatric patient is more likely to carry a genetic mutation. A scoring system such as the Mo-CVID score could help physicians prioritize genetic testing. Genetic analysis in CVID patients can help stratify patients into different disease entities to predict complications and prognosis, ensure appropriate genetic counseling, and personalize treatment.

PMID:40079712 | DOI:10.1002/eji.202451433

Breast Cancer Res. 2025 Mar 11;27(1):36. doi: 10.1186/s13058-025-01988-w.

ABSTRACT

BACKGROUND: The ataxia-telangiectasia mutated (ATM) kinase phosphorylates and activates several downstream targets that are essential for DNA damage repair, cell cycle inhibition and apoptosis. Germline biallelic inactivation of the ATM gene causes ataxia-telangiectasia (A-T), and heterozygous pathogenic variant (PV) carriers are at increased risk of cancer, notably breast cancer. This study aimed to investigate whether DNA methylation profiling can be useful as a biomarker to identify tumors arising in ATM PV carriers, which may help for the management and optimal tailoring of therapies of these patients.

METHODS: Breast tumor enriched DNA was prepared from 2 A-T patients, 27 patients carrying an ATM PV, 6 patients carrying a variant of uncertain clinical significance and 484 noncarriers enrolled in epidemiological studies conducted in France and Australia to investigate genetic and nongenetic factors involved in breast cancer susceptibility. Genome-wide DNA methylation analysis was performed using the Illumina Infinium HumanMethylation EPIC and 450K BeadChips. Correlation between promoter methylation and gene expression was assessed for 10 tumors for which transcriptomic data were available.

RESULTS: We found that the ATM promoter was hypermethylated in 62% of tumors of heterozygous PV carriers compared to the mean methylation level of ATM promoter in tumors of noncarriers. Gene set enrichment analyses identified 47 biological pathways enriched in hypermethylated genes involved in neoplastic, neurodegenerative and metabolic-related pathways in tumor of PV carriers. Among the 327 differentially methylated promoters, promoters of ARHGAP40, SCGB3A1 (HIN-1), and CYBRD1 (DCYTB) were hypermethylated and associated with a lower gene expression in these tumors. Moreover, using three different deep learning algorithms (logistic regression, random forest and XGBoost), we identified a set of 27 additional biomarkers predictive of ATM status, which could be used in the future to provide evidence for or against pathogenicity in ATM variant classification strategies.

CONCLUSIONS: We showed that breast tumors that arise in women who carry an ATM PV display a specific genome-wide DNA methylation profile. Specifically, the methylation pattern of 27 key gene promoters was predictive of ATM PV status of the women. These genes may also represent new medical prevention and therapeutic targets for these women.

PMID:40069712 | DOI:10.1186/s13058-025-01988-w

Contemp Clin Trials Commun. 2025 Feb 15;44:101462. doi: 10.1016/j.conctc.2025.101462. eCollection 2025 Apr.

ABSTRACT

BACKGROUND: Streptococcus pneumoniae causes infections especially in patients with immunodeficiency or specific comorbidities. Most could be avoided through pneumococcal vaccination (PV), but PV coverage is only 20 % in France. Many studies assess methods on vaccination coverage improvement, but none evaluates pharmacist-physician collaboration in hospital on PV coverage of inpatients at-risk of invasive pneumococcal disease (IPD).

METHODS: This study is a multicentric stepped-wedged randomized trial involving 12 units in 9 French hospitals (3 university and 6 local) during 4 periods of 90 days each. Three clusters will be made, each composed randomly of clinical and surgical units from one university hospital and clinical and surgical units of 2 local hospitals. For each period, one unit will have to include 16 non-vaccinated inpatients at risk of IPD. Patients in the control phase will receive usual care. During the interventional phase, the pharmacist will inform the physician on PV necessity, who will report recommendation and prescribe it at discharge. The pharmacist will perform a consultation and send a discharge letter to the patient’s community pharmacist. The primary outcome will assess the impact of intervention on PV coverage after 6 months. Secondary outcomes will evaluate vaccines dispensing, uncompleted protocol rate and intervention process. A subgroup analysis between university and local hospitals and clinical and surgical units, respectively will be made.

DISCUSSION: This study will assess the impact of medico-pharmaceutical collaboration in hospital on PV coverage in inpatients at risk of IPD. Hospitalization could be a way to promote vaccination and enhance healthcare system performance.

TRIAL REGISTRATION: Clinicaltrials.gov, NCT05060146. Registered on September 16th, 2021.

PMID:40065836 | PMC:PMC11891599 | DOI:10.1016/j.conctc.2025.101462