Manish Butte

Sci Rep. 2025 Dec 9. doi: 10.1038/s41598-025-31533-w. Online ahead of print.

ABSTRACT

This study aimed to identify and validate key target genes of Astragalus membranaceus and Ephedra in pediatric obesity-associated asthma using integrated bioinformatics and network pharmacology approaches, with the goal of informing potential therapeutic strategies. Gene expression datasets related to pediatric obesity (GSE205668, GSE104815) and asthma (GSE147878, GSE143303) were analyzed. Candidate genes were obtained by overlapping differentially expressed genes with known targets of Astragalus membranaceus and Ephedra. Machine learning algorithms and expression analyses were applied to refine the list of key genes. Two nomogram prediction models were constructed based on these genes and assessed for diagnostic efficacy. Subsequent analyses included functional enrichment, immune cell infiltration profiling, molecular docking, and validation through reverse transcription quantitative PCR (RT-qPCR). The genes AKR1C3 and KYNU were identified as key targets associated with both pediatric obesity and asthma. RT-qPCR results demonstrated significantly elevated expression of AKR1C3 and KYNU in samples from individuals with obesity-related asthma (P < 0.01). The developed nomogram models accurately predicted disease risk. Functional enrichment analysis indicated that these genes were co-enriched in pathways including allograft rejection in the context of obesity and primary immunodeficiency in the context of asthma. Immune cell profiling indicated alterations in 18 immune cell types in pediatric obesity and 5 in asthma. Molecular docking results indicated that kaempferol and apigenin exhibited strong binding affinities with AKR1C3, while canavanine effectively targeted KYNU, with a binding energy of – 9.5 kcal/mol between AKR1C3 and kaempferol. AKR1C3 and KYNU were identified and experimentally validated as potential therapeutic targets in pediatric asthma associated with obesity. These findings support the therapeutic relevance of A. membranaceus and Ephedra-derived compounds in modulating key molecular pathways implicated in this comorbid condition.

PMID:41366037 | DOI:10.1038/s41598-025-31533-w

Clin Rev Allergy Immunol. 2025 Dec 6;68(1):106. doi: 10.1007/s12016-025-09116-4.

ABSTRACT

Secondary antibody deficiency (SAD) represents a substantial yet under-recognised global healthcare burden. It is more prevalent than primary antibody deficiency, but frequently under-diagnosed and variably managed worldwide. Prompt diagnosis is often hindered by insufficient awareness among clinicians, lack of global consensus on screening/monitoring for SAD among at-risk patients, inadequate clinical immunology services and lack of standardised referral pathways/protocols. Management practices vary widely, with little international agreement, particularly regarding threshold to initiate immunoglobulin replacement, as well as regimen, dosage and frequency of immunoglobulin administration. Subcutaneous immunoglobulin (SCIg) replacement emerged as a promising alternative to traditional intravenous immunoglobulin (IVIg) replacement. IVIg requires monthly infusions in inpatient/day-hospital settings leading to high peak serum IgG and subsequent variations with end-of-cycle ‘wear-off effect’, causing more systemic side effects and increased risk of breakthrough infections, and disruption of daily life and employment. While previous evidence was largely derived from primary antibody deficiency, recent comparative studies on SAD patients indicate that SCIg replacement, through weekly self-administered infusions, can achieve more stable and higher trough serum IgG, lower infection rates, fewer systemic adverse reactions and enhanced health-related quality-of-life compared to IVIg. There is also potential cost-savings from the use of SCIg replacement. This review emphasises the urgent need for standardised guidelines on screening/diagnosis and treatment of SAD, and large-scale multi-centre trials and real-world studies on IVIg vs SCIg replacement among SAD patients, which will facilitate better identification, management, and health-outcomes for SAD patients, ultimately alleviating a significant global health challenge through coordinated clinical, research, and policy efforts.

PMID:41351689 | DOI:10.1007/s12016-025-09116-4

J Immunother Cancer. 2025 Dec 4;13(12):e013024. doi: 10.1136/jitc-2025-013024.

ABSTRACT

BACKGROUND: Challenges to developing immunotherapies for acute myeloid leukemia (AML) include the identification of suitable target antigens due to on-target-off-leukemia toxicity. CD70, expressed on AML bulk and leukemic stem cells with limited expression on healthy cells, has emerged as a promising target.

METHODS: This study evaluated CD70 as a target for NK-cell-based immunotherapy using a sugar-engineered antibody (PF-08046040, SEA-CD70). CD70 surface expression was assessed in primary AML samples by multiparameter flow cytometry. The cytotoxic capacity of SEA-CD70 was analyzed through antibody-dependent cellular cytotoxicity (ADCC) assays using AML cell lines, primary AML samples, and a severe combined immunodeficiency (SCID) mouse xenograft model. The effects of cytokines on CD70 expression and ADCC were investigated by exposing AML cells to conditioned medium (CM) derived from activated T cells or recombinant cytokines.

RESULTS: Flow cytometry revealed CD70 expression ranging from 0.2% to 89.6% (median=7.0%, n=86) in primary AML cells across genetic subgroups; this expression remained unchanged at relapse (median=3.9%, n=14). SEA-CD70 showed potent, dose-dependent cytotoxicity against AML cell lines, primary cells, and in an SCID mouse model, which correlated with CD70 expression levels. Notably, AML cells exposed to CM from activated T cells upregulated CD70. TNF-α was identified as the driver of CD70 upregulation, translating into enhanced ADCC against AML cells (cytotoxicity w/o TNF-α = 17.9% vs with TNF-α = 34.3%, n=13-15). Conversely, IFN-γ exposure led to reduced ADCC (cytotoxicity w/o IFN-γ = 17.9% vs with IFN-γ = 9.2%, n=15), which is attributed to increased expression of NK inhibitory receptor ligands (HLA-ABC, HLA-E). Blocking of the corresponding inhibitory NK receptors (KIR/CD158b and NKG2A) partially reversed this effect. Similar findings were observed with a CD33-directed antibody, indicating a universal resistance mechanism against ADCC-based immunotherapy in AML.

CONCLUSIONS: CD70 is a promising target for NK cell-based immunotherapy in AML. However, IFN-γ-dependent upregulation of HLA molecules on AML cells contributes to resistance to ADCC. These findings underscore the need for rationale combination strategies in clinical trials to overcome this inducible immune escape mechanism.

PMID:41344992 | DOI:10.1136/jitc-2025-013024

J Allergy Clin Immunol Glob. 2025 Oct 30;5(1):100591. doi: 10.1016/j.jacig.2025.100591. eCollection 2026 Jan.

ABSTRACT

BACKGROUND: IL2RG and JAK3 mutations cause T-cell-negative, B-cell-positive, natural killer cell-negative severe combined immunodeficiency (SCID). Cell therapies such as hematopoietic stem cell transplantation (or gene therapy for IL2RG deficiency) can effectively restore T-cell immunity but-when performed without myeloablation-may leave residual immune defects. These include persistent B-cell dysfunction, poor innate lymphoid cell recovery, and poor reconstitution of secondary lymphoid organs. Severe/recurrent warts may also occur in the long term.

OBJECTIVE: We present 3 IL2RG SCID cases complicated by lymphedema and discuss possible hypotheses of this rare complication.

METHODS: We describe 3 patients with IL2RG SCID who developed lymphedema: 2 after unconditioned cell therapy and 1 with a hypomorphic mutation who remained untreated. Clinical presentation, immunologic data, imaging, and transplant history were reviewed and compared with published data.

RESULTS: Lymphedema affected the lower limbs and varied in severity, with one case complicated by recurrent dermohypodermitis and Streptococcus mitis sepsis.

CONCLUSION: Lymphedema is a rare but potentially disabling complication of IL2RG/JAK3 SCID, affecting long-term quality of life. Hypothetically, low/absent levels of innate lymphoid cells-particularly lymphoid tissue inducer cells, a subset of innate lymphoid cells-may be a contributing factor in the pathogenesis of lymphedema in IL2RG/JAK3 SCID.

PMID:41341763 | PMC:PMC12670891 | DOI:10.1016/j.jacig.2025.100591

bioRxiv [Preprint]. 2025 Nov 18:2025.11.18.688830. doi: 10.1101/2025.11.18.688830.

ABSTRACT

Pathogenic variants in the Autoimmune Regulator (AIRE) gene cause Autoimmune Polyendocrine Syndrome Type 1 (APS-1), a rare primary immunodeficiency disease with symptoms including hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candidiasis. AIRE increases the expression and presentation of tissue-specific genes expressing ‘self’ antigens in the developing T cell niche, thus triggering the elimination of self-reactive T cells and preventing autoimmunity. Earlier diagnoses can benefit patients, and APS-1 diagnosis by AIRE sequencing is increasingly common. However, two thirds of reported clinical variants are missense, and more than half of these are “variants of uncertain significance” (VUS). Cell-based variant functional assays can provide strong evidence towards more informative variant classification, but these are carried out reactively, often years after clinical presentation. By contrast, proactively assessing all possible missense variants could provide immediate evidence to guide genetic diagnosis, even for never-before-seen variants. Here we used an insulin promoter-driven reporter to proactively assess the function of 9790 AIRE missense variants. The resulting AIRE variant effect map both validates and extends current biochemical knowledge, concords with pathogenicity annotations, and provides proactive evidence for 70% of previously-reported VUS. Placing our map in the context of both an international APS-1 cohort and the UK BioBank revealed quantitative genotype-phenotype correlations. Using current guidelines, we provide classifications for 32% of current VUS. Together, our proactive resource of AIRE variant impacts offers the potential to improve patient outcomes via more rapid and definitive APS-1 diagnosis.

PMID:41332640 | PMC:PMC12667976 | DOI:10.1101/2025.11.18.688830

Scand J Immunol. 2025 Dec;102(6):e70074. doi: 10.1111/sji.70074.

NO ABSTRACT

PMID:41327753 | DOI:10.1111/sji.70074

Clin Rev Allergy Immunol. 2025 Dec 1;68(1):105. doi: 10.1007/s12016-025-09099-2.

ABSTRACT

Common Variable Immunodeficiency Disorders (CVID) are the most frequent symptomatic Primary Immunodeficiency (PID) in adults and children. Patients with CVID present with predominant antibody deficiency with varying degrees of impaired cellular immunity. CVID was previously a diagnosis of exclusion, which led to considerable uncertainty about which patients would qualify for subcutaneous or intravenous immunoglobulin (SCIG/IVIG) replacement. Over the last twelve years, several sets of diagnostic criteria have been published which identify these disorders with greater precision. These new CVID diagnostic criteria assist with decisions on treatment, particularly SCIG/IVIG replacement. With the advent of massively parallel genome sequencing technologies, it has become apparent that a significant proportion of individuals with a CVID phenotype have an underlying causative genetic defect. If such a pathogenic variant is identified, these individuals are removed from the overarching diagnosis of CVID and are deemed to have a CVID-like disorder caused by a specific Inborn Error of Immunity (IEI). New Zealand has had a long-standing customized PID genetic testing program. Two novel autosomal dominant pathogenic variants causing CVID-like disorders, consequent to haploinsufficiency of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NFKB1) and Transcription Factor 3 (TCF3), were identified in New Zealand families. The latter pathogenic variant was shown to have an epistatic interaction with TNFRSF13B (TACI) in a patient with a digenic CVID-like disorder. Epistasis is the synergistic, non-linear interaction between two or more genetic loci, leading to much more severe (or much milder) disease. This perspective reviews the current understanding of these disorders with contributions from three New Zealand-based studies: The Prospective NZ CVID and the NZ hypogammaglobulinemia sub-studies as well as a large retrospective case series of Transient Hypogammaglobulinemia of Infancy (THI). These clinical and genomic studies have offered insights into the complexities of these rare PIDs. This review examines current areas of uncertainty in the diagnosis of of these disorders.

PMID:41324804 | DOI:10.1007/s12016-025-09099-2

Pediatr Transplant. 2025 Dec;29(8):e70234. doi: 10.1111/petr.70234.

ABSTRACT

BACKGROUND: Schimke Immuno-Osseous Dysplasia Is a Rare Autosomal Recessive Multisystem Disorder Caused by Biallelic Pathogenic Variants in the SMARCAL1 Gene, Which Encodes a DNA Annealing Helicase Essential for Replication Fork Stability and Genomic Maintenance. Loss of SMARCAL1 Function Leads to Genomic Instability, Resulting in a Characteristic Clinical Triad of Disproportionate Short Stature, Steroid-Resistant Nephrotic Syndrome and Immunodeficiency. Kidney Transplantation Is the Standard Treatment for End-Stage Renal Disease in Schimke Immuno-Osseous Dysplasia. However, the Underlying Genomic Fragility and Immunodeficiency Heighten the Risk of Post-Transplant Complications, Particularly Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disorder.

METHOD: We Report the Case of a 7-Year-Old Girl With Genetically Confirmed Schimke Immuno-Osseous Dysplasia Who Developed Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma Eight Months Following Maternal Kidney Transplantation, Despite Reduced-Intensity Immunosuppression. Rituximab Therapy Resulted in Complete Remission, but Required the Withdrawal of all Immunosuppressive Agents, Thereby Posing a Risk of Kidney Graft Loss.

RESULT: In the Context of Primary Immunodeficiency and the Development of Post-Transplant Lymphoproliferative Disorder in Such a Setting, the Patient Subsequently Underwent Haploidentical Hematopoietic Stem Cell Transplantation From the Mother, Using an αβ T-Cell-Depleted Graft and a Nephrotoxicity-Sparing Conditioning Regimen. Full Donor Chimerism Was Achieved by Day 28. Immune Reconstitution Occurred Within One Year. At 27 Months After Hematopoietic Stem Cell Transplantation She Remains in Remission With Preserved Kidney Function and no Ongoing Immunosuppression.

CONCLUSION: This Case Highlights the Feasibility of Haploidentical Hematopoietic Stem Cell Transplantation as a Curative Salvage Strategy for Immunosuppression-Free Survival After Kidney Transplantation in Patients With Schimke Immuno-Osseous Dysplasia.

PMID:41320805 | DOI:10.1111/petr.70234

Med Mycol J. 2025;66(4):205-211. doi: 10.3314/mmj.25-00011.

ABSTRACT

This report presents the case of a Thai male in his twenties presenting prolonged fever, generalized lymphadenopathy and hepatosplenomegaly. Blood cultures isolated Campylobacter jejuni, while lymph node cultures isolated Histoplasma capsulatum. A gene panel for immunodeficiency revealed nuclear factor kappa B subunit 1 (NFKB1) deficiency, leading to a final diagnosis of common variable immunodeficiency (CVID) due to autosomal dominant NFKB1 deficiency. The patient was initially treated with amphotericin B (0.7 mg/kg/day) for 3 weeks, followed by itraconazole 200 mg orally twice daily, and received intravenous azithromycin 500 mg once daily for C. jejuni bacteremia for 14 days. After three months of treatment, the patient demonstrated partial clinical and radiologic improvement. Additionally, intravenous immunoglobulin was administered to treat CVID. After 12 months of itraconazole, the follow-up computed tomography showed reduced lymphadenopathy to subcentimetric nodes and resolved hepatomegaly. Patients with disseminated atypical infections should be evaluated for primary immunodeficiency disorders, even when considered healthy.

PMID:41320321 | DOI:10.3314/mmj.25-00011

J Clin Immunol. 2025 Nov 28. doi: 10.1007/s10875-025-01966-z. Online ahead of print.

ABSTRACT

PURPOSE: Despite well-conducted replacement therapy with polyvalent immunoglobulins (IgRT), some patients with primary immunodeficiencies (PID) continue to experience recurrent or chronic infections. IgA and IgM, essential for mucosal and complement-mediated immunity, are absent or minimal in standard immunoglobulin products. The aim of this study is to evaluate the safety and clinical evolution profiles in PID patients with undetectable IgA/IgM levels and persistent infections despite standard IgRT, after introduction of an IgA- and IgM-enriched immunoglobulin preparation (IgGAM, Pentaglobin^®).

METHODS: A compassionate use program (CUP) in France enrolled 20 PID patients with undetectable IgA/IgM levels, receiving IgGAM IV infusions every 7-14 days. Tolerance, infection frequency, hospitalizations, and biological markers (Ig levels, complement activation, salivary IgA) were analyzed prospectively.

RESULTS: Twenty patients were included in the CUP at the time of analysis. No severe adverse event was reported. Half of the patients experienced mild to moderate hypersensitivity symptoms. Mean antibiotic courses dropped from 5.4 to 2.3/year (p = 0.0009) and mean number of hospitalizations decreased from 2.6 to 1.2/year (p = 0.01). Median serum IgA and IgM levels increased three months after IgGAM start. IgM and low levels of IgA were detected in saliva samples, suggesting at least a transient transfer of IgA/IgM from IgGAM into mucosal fluids.

CONCLUSION: In patients with severe PID and undetectable IgA/IgM, IgGAM was associated with reduced infections and hospitalizations. Controlled studies are needed to confirm the benefit of IgA/M enriched immunoglobulin preparations in PID patients with persistent and/or recurrent respiratory or digestive infections.

PMID:41315117 | DOI:10.1007/s10875-025-01966-z