Manish Butte

Expert Rev Clin Immunol. 2025 Oct 13. doi: 10.1080/1744666X.2025.2575361. Online ahead of print.

ABSTRACT

INTRODUCTION: Inborn errors of immunity with atopic phenotypes (IEIwA) represent a growing and complex subset of monogenic disorders that manifest primarily through severe and multifaceted allergic symptoms. These conditions bridge the fields of immunodeficiency and atopy, posing significant diagnostic and therapeutic challenges.

AREAS COVERED: A literature search was performed via the online database PubMed, including all publication years 2021-2024, with the objective of identifying the most recent advancements in the field of IEIwA. This review provides an updated synthesis of the immunogenetic mechanisms underlying IEIwA, categorizing them by pathophysiological pathways, including impaired T cell receptor signaling, cytokine dysregulation, T cell repertoire restrictions, regulatory T cell dysfunction, metabolic abnormalities, and skin barrier defects. Advances in genomic technologies, especially whole exome/genome sequencing, have refined the classification and recognition of these disorders. Moreover, the review highlights red flags that may aid in differentiating monogenic IEIwA from multifactorial allergic conditions. Emerging targeted therapies, such as monoclonal antibodies and small molecules, offer new avenues for precision medicine, though curative treatments like hematopoietic stem cell transplantation remain essential for many conditions.

EXPERT OPINION: This review underscores the need for heightened awareness, early recognition, and tailored management strategies to improve outcomes in patients with IEIwA.

PMID:41082333 | DOI:10.1080/1744666X.2025.2575361

Front Med (Lausanne). 2025 Sep 25;12:1569810. doi: 10.3389/fmed.2025.1569810. eCollection 2025.

ABSTRACT

BACKGROUND: Common variable immune deficiency disorder (CVID) and X-linked agammaglobulinemia (XLA) are the most prevalent predominantly antibody deficiencies (PADs). Analysis of the TACI/TNFRSF13B gene in CVID and BTK genes in XLA patients using Sanger sequencing can help make specific diagnoses of these cases. The study aimed to find the TACI and BTK gene mutations and their allelic variations associated with CVID and XLA patients.

METHODS: This cross-sectional study was conducted on clinically suspected PAD patients who attended the Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh, from September 2022 to August 2023. Serum immunoglobulin levels, immunophenotyping by flow cytometry, and PCR were conducted in the Department of Microbiology and Immunology at BSMMU. Genetic analysis of the TACI and BTK genes was conducted using Sanger sequencing at DNA Solutions Limited, Dhaka, Bangladesh. The sequencing results were validated using the NCBI GenBank.

RESULTS: Of 35 clinically suspected PAD patients, 15 (42.86%) were diagnosed as PAD patients. Within this group, seven (46.67%) were diagnosed with CVID, seven (46.67%) with XLA, and one (6.66%) with agammaglobulinemia other than XLA. The analysis of the TACI gene revealed no pathogenic variants in the CVID patients. Upon analyzing exons 2 to 19 of the BTK gene, seven pathogenic/likely pathogenic mutations were detected, consisting of four nonsense and three missense mutations. Among these, three were found to be novel mutations, including two missense and one nonsense mutation.

CONCLUSION: The genetic analysis of the TACI gene in CVID patients revealed no pathogenic variants. The BTK gene displayed heterogeneous mutations, with nonsense mutations being the most prevalent. In this cohort, XLA patients presented three de novo point mutations.

PMID:41080960 | PMC:PMC12507743 | DOI:10.3389/fmed.2025.1569810

Front Immunol. 2025 Sep 25;16:1656240. doi: 10.3389/fimmu.2025.1656240. eCollection 2025.

ABSTRACT

BACKGROUND: Zeta-chain-associated protein kinase 70 (ZAP70) deficiency is a rare autosomal recessive T⁺B⁺NK⁺ combined immunodeficiency characterized by heterogeneous clinical and immunologic phenotypes. Because of the limited number of reported cases, data guiding optimal management and hematopoietic stem cell transplantation (HSCT) strategies remain scarce.

METHODS: We retrospectively reviewed all patients with genetically confirmed ZAP70 deficiency treated at King Faisal Specialist Hospital and Research Centre. Data on pre-HSCT clinical and immunologic features, transplant characteristics, post-HSCT complications, immune reconstitution, and long-term outcomes were recorded.

RESULTS: Thirteen patients with a median age at symptom onset of 1 month were identified. The most frequent initial presentations were recurrent respiratory infections and cutaneous manifestations. Autoimmune complications and lymphoproliferation were observed in several patients. Eleven of thirteen patients (84.6%) exhibited profound CD8⁺ T-cell lymphopenias and two had near-normal CD8⁺ T-cell counts with impaired T-cell function. Eleven patients underwent HSCT, including seven from Human Leukocyte Antigen (HLA)-matched family donors, two from one-antigen mismatched related donors, one from a haploidentical mother (matched for graft-versus-host disease risk but mismatched for rejection), and one from an unrelated cord blood donor. Two patients required a second transplant because of poor immune reconstitution. Of the 11 patients who underwent HSCT, 8 (73%) remain alive with a median follow-up of 7 years (range, 1-15), and most demonstrated resolution of clinical manifestations.

CONCLUSION: HSCT remains the only curative treatment for ZAP70 deficiency. Myeloablative conditioning regimens appear to promote more robust and durable immune reconstitution. In critically ill patients with severe infections or end-organ damage, reduced-intensity or unconditioned HSCT can be considered as a life-saving approach, although subsequent interventions might be necessary.

PMID:41080547 | PMC:PMC12507918 | DOI:10.3389/fimmu.2025.1656240

Front Pediatr. 2025 Sep 25;13:1702168. doi: 10.3389/fped.2025.1702168. eCollection 2025.

NO ABSTRACT

PMID:41080062 | PMC:PMC12508774 | DOI:10.3389/fped.2025.1702168

Immunol Res. 2025 Oct 10;73(1):141. doi: 10.1007/s12026-025-09699-2.

ABSTRACT

Common Variable Immunodeficiency (CVID) is the most frequently encountered symptomatic primary immunodeficiency in clinical practice, presenting with heterogeneous clinical and genetic features. While traditionally considered polygenic, recent advances in genomic technologies have revealed monogenic causes in a significant subset of patients. This study aimed to investigate the genetic background of adult patients diagnosed with CVID or CVID-like phenotypes, using clinical exome sequencing (CES), focusing on atypical and syndromic presentations. Thirty adult patients fulfilling the ESID/PAGID criteria for CVID underwent CES. Genetic analysis targeted 451 immune-related genes, with variants interpreted according to ACMG guidelines. Pathogenicity was confirmed with Sanger sequencing. We detected potentially disease-related variants (TNFRSF13B, BTK, RAG1, SAMD9, NFKB2, PRKDC, CFTR, FCN3, IFIH1, ITGA3, and TNFRSF1A) in 12 of the 30 patients (40%). TNFRSF13B was the most frequently mutated gene among these patients. Deep phenotyping analyses revealed atypical findings included a hemizygous BTK variant mimicking CVID, a homozygous RAG1 variant consistent with leaky SCID, and a heterozygous SAMD9 variant not presenting with MIRAGE phenotype, and a homozygous ITGA3 insertion region variant that suggested a mild form of ILNED syndrome. Variants in CFTR, FCN3, and TNFRSF1A further expand the phenotypic spectrum, highlighting overlap between immunodeficiency and immune dysregulation syndromes in adulthood. A substantial proportion of adult patients with CVID-like phenotypes harbor variants in genes beyond the classical CVID-associated loci. Our findings support the utility of broad genetic screening in adult-onset antibody deficiency, particularly when non-infectious complications are present. Molecular diagnosis facilitates accurate classification, guides personalized treatment, and aids in genetic counseling.

PMID:41071379 | DOI:10.1007/s12026-025-09699-2

PLoS One. 2025 Oct 9;20(10):e0329585. doi: 10.1371/journal.pone.0329585. eCollection 2025.

ABSTRACT

Treatment options for hereditary angioedema (HAE) have evolved due to discoveries in basic and clinical research. HAE clinical guidelines emphasize optimizing quality of life through attack prevention strategies that include long-term prophylaxis. We sought to identify barriers to and promoters of research translation into HAE clinical practice that may inform efforts to improve patient care. We interviewed US allergy/immunology clinicians who completed an online continuing medical education activity on HAE or were identified through healthcare provider directories. Interviews focused on clinicians’ experiences translating HAE research results into clinical care. Deidentified interview transcripts were coded and analyzed to detect emergent themes using Dedoose software. Thematic analysis of 15 interviews showed that insurance prior authorization for HAE medications, including those for long-term prophylaxis, was perceived as the biggest barrier to evidence-based care. Other prominent barriers were laboratory testing difficulties, time constraints, and deficits in both primary care provider and patient understanding of HAE. Promoters of research translation included availability of medication samples, route/frequency of drug administration, and shared decision-making. Clinicians used different resources to learn about HAE, including online chat rooms. None of the clinicians used a validated instrument to assess HAE-related quality of life. Perceptions of the usefulness of HAE clinical guidelines were mixed. A range of factors act as barriers and promoters to research translation into clinical care for patients with HAE. Our findings have implications for interventions to enhance the delivery of evidence-based care for patients with HAE.

PMID:41066422 | DOI:10.1371/journal.pone.0329585

Mol Biol Rep. 2025 Oct 9;52(1):998. doi: 10.1007/s11033-025-11094-x.

ABSTRACT

Ataxia-Telangiectasia (A-T) is caused by biallelic Ataxia-Telangiectasia Mutated (ATM) protein mutations and is hallmarked by neurodegeneration, immunodeficiency and cancer susceptibility. Emerging work suggests that non-coding RNAs are integral to the ATM driven DNA damage response, yet the scope of non-coding RNA perturbation in A-T has not systematically mapped. This study is done to chart and synthesize all primary evidence on ncRNA dysregulation in A-T and to identify mechanistic gaps and research priorities. The evidence base comprises a total of five studies focused exclusively on microRNAs and long non-coding RNAs. Baseline sequencing of 20 patients revealed consistent downregulation of miR-195-5p, miR-30a-5p and miR-342-3p. Low dose γ-irradiation of ATM-null lymphoblastoid cell lines produced an exaggerated bidirectional shift (8 microRNAs upregulated, 6 downregulated) versus wild-type, whereas primary T-cells showed largely ATM independent rises of miR-34a-5p and miR-182-5p. A lymphoblastoid cell lines study distinguished 22 recessive or dominant radiation-responsive microRNAs. Long non-coding RNAs profiling identified 149 transcripts that require functional ATM for induction and three uniquely upregulated in A-T cells. No circular RNA study in A-T is observed till date. The ncRNA research in A-T is nascent with five studies present a miRNA dysregulation and an ATM-dependent lncRNA surge that is lost in A-T, but leave circRNAs, neuronal tissues and functional validation unexplored. Intermediate dose stress models, total and small RNA-seq under DNA damage and oxidative stress, and CRISPR rescue/knockout screens in patient derived organoids are immediate priorities for exploring the role of ncRNAs as therapeutic targets in A-T.

PMID:41065894 | DOI:10.1007/s11033-025-11094-x

J Clin Immunol. 2025 Oct 9;45(1):142. doi: 10.1007/s10875-025-01944-5.

NO ABSTRACT

PMID:41065887 | DOI:10.1007/s10875-025-01944-5

Health Sci Rep. 2025 Oct 6;8(10):e71318. doi: 10.1002/hsr2.71318. eCollection 2025 Oct.

ABSTRACT

BACKGROUND AND AIMS: Biomarkers are essential tools in the diagnosis and management of various diseases. Rheumatoid arthritis (RA) is a systemic inflammatory disorder that frequently results in damage to joints and organs. Here, we examined potential biomarkers and therapeutic agents for RA patients.

METHODS: Three microarray datasets and clinical data for synovial tissue were sourced from the publicly available Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in RA versus osteoarthritis (OA) patients were identified, followed by functional enrichment analysis, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network analysis to explore DEG-associated pathways and identify hub genes. Furthermore, serum levels of relevant antibodies were measured using enzyme-linked immunosorbent assay (ELISA). Additionally, potential therapeutic compounds for RA were predicted using the Connectivity Map (CMap) database, and molecular docking was conducted to assess their binding affinities with target proteins.

RESULTS: A total of 409 DEGs were identified, with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GSEA analyses highlighting enrichment in cytokine activity, cytokine-receptor interactions, and the primary immunodeficiency pathway. Five key modules and hub genes were found using Cytoscape, and expression levels of CD40LG, ITGAX, and PTPRC were validated with another GEO data set. ELISA confirmed elevated serum CD40LG antibody levels in RA patients, suggesting its potential as a biomarker, especially in those with interstitial lung disease (ILD) or bone destruction. Connectivity map analysis identified small molecules that may reverse DEGs, and molecular docking showed emetine, oligomycin, cromoglicic acid, sulfinpyrazone, buspirone, and chlorogenic acid had favorable binding energies.

CONCLUSION: CD40LG is a potential biomarker for RA, especially in patients with ILD or bone damage. Emetine, oligomycin, cromoglicic acid, sulfinpyrazone, buspirone, and chlorogenic acid are potential therapeutic agents for RA treatments.

PMID:41064206 | PMC:PMC12500530 | DOI:10.1002/hsr2.71318

JBJS Essent Surg Tech. 2025 Oct 8;15(4):e24.00011. doi: 10.2106/JBJS.ST.24.00011. eCollection 2025 Oct-Dec.

ABSTRACT

BACKGROUND: Primary bone tumors frequently occur in the proximal tibia, ranking as the second most common location after the distal femur¹. Challenges to treatment include the proximity of neurovascular structures, limited soft-tissue coverage, compromised knee extension, and postoperative complications^1-8. The present video article describes proximal tibial resection for the treatment of a bone tumor and prosthetic reconstruction combined with a medial gastrocnemius flap.

DESCRIPTION: Proximal tibial resection is performed with use of an anteromedial approach. After defining the resection level, the tumor is removed en bloc with wide free margins. Reconstruction is performed with use of a megaprosthesis, and the medial gastrocnemius flap is utilized for covering the prosthesis and for reconstruction of the extensor apparatus.

ALTERNATIVES: Osteoarticular allografts and allograft-prosthesis composites allow restoration of bone stock and direct biological reattachment of host tendons, ligaments, and capsule. Autografting is performed using the fibula as a donor site. Custom-made implants can be designed according to the patient’s anatomy. Amputation should be considered when the neurovascular bundle is widely involved by the tumor.

RATIONALE: In contrast to alternative treatments, megaprosthetic reconstructions offer several advantages: technical simplicity, immediate weight-bearing, and shorter immobilization. Additionally, megaprostheses do not carry the risk of allograft-related complications, such as nonunion, fracture, subchondral collapse, articular cartilage degeneration, and instability.

EXPECTED OUTCOMES: Patients with metallic endoprostheses demonstrate lower rates of complications and amputation, as well as higher patient survival rates, compared with those treated with allograft reconstructions^7,9,10. The advancements in technology and design since 1977 have contributed to reduced mechanical stress at the bone-prosthesis interface and decreased rates of mechanical or structural failure^3,11,12. However, despite advancements in design, proximal tibial prosthetic reconstructions continue to exhibit the least favorable outcomes and function among all limb-salvage procedures, accompanied by the highest rate of complications^1,9-11. Studies report survival rates ranging from 45% to 82% at 5 years and 45% to 78% at 10 years^1,13, with rates of revision for infection and loosening ranging from 40% at 5 years to 73% at 15 years^1,10,13. Various techniques are utilized for attaching the extensor mechanism of the knee and providing coverage for proximal tibial reconstructions^7,8,10,14,15. Various studies have emphasized the importance of direct attachment of the extensor mechanism to the megaprosthesis, which facilitates initial mechanical stability crucial for healing and scarring^7,10,16. Pedicled muscle flaps, particularly the medial or lateral gastrocnemius, have commonly been utilized to supply blood to aid wound healing and to biologically reconstruct the extensor mechanism^7-9. Despite some patients experiencing increased extension lag, gradual improvement in function¹⁷ was observed during follow-up. In our experience with 225 proximal tibial resections, survival of megaprosthetic reconstructions was 82% and 78% at 5 and 10 years, respectively, without any difference between the use of a fixed versus rotating hinge¹. However, the rate of good or excellent functional outcomes, as measured according to the Musculoskeletal Tumor Society (MSTS) system¹⁷, was significantly higher with use of a rotating hinge. Infection was, as expected, the most frequent complication, occurring in 27 patients (12%), followed by aseptic loosening (13 patients, 6%), rupture of the extensor mechanism (6 patients, 3%), breakage of the prostheses (4 patients, 1.6%), and wound dehiscence (4 patients, 1.6%)¹.

IMPORTANT TIPS: Preoperative evaluation and imaging. Perform a thorough history and physical examination, assess for evidence of a syndrome or family history, and utilize imaging studies to evaluate the tumor.Patient positioning and incision planning. Position the patient supine to ensure full access to the proximal tibia. Prepare and drape the patient; center the incision on the mass through an anteromedial approach including the biopsy tract and perform a longitudinal incision.Harvest the gastrocnemius flap. After identifying the proximal vessels, proceed to dissect the gastrocnemius flap, which is typically straightforward and rapid (even after tumor removal).Dissection of soft tissue and definition of the tumor resection margin. Protect and retract the medial gastrocnemius flap and then isolate and protect the popliteal and posterior tibial vessels.Deep dissection and articular resection. If staging and preoperative planning indicated no evidence of tumor inside the joint, intra-articular knee resection should be conducted. Arthrotomy is performed through a parapatellar approach, and the cruciate ligaments are cut close to the femoral attachment.Tumor removal. After the specimen with the tumor is freed circumferentially, identify the osteotomy level and dissect any remaining structures connected with proximal tibia to remove the entire tumor.Inspection and hemostasis. Evaluate for hemostasis and send the specimen for pathologic analysis. Prepare for the reconstructive phase and close the surgical site.Proximal tibial reconstruction with a modular endoprosthesis. Tumor mega-endoprostheses are appealing because of their versatility, ability to yield favorable functional outcomes, ability to allow immediate weight-bearing, and possible cost-effectiveness.Reconstruction of the extensor mechanism. The commonly utilized approach involves employing a medial gastrocnemius flap.Monitoring and postoperative care. Postoperative monitoring is crucial. A strict rehabilitation protocol with immobilization in full extension for 4 weeks followed by progressive mobilization for 3 months is critical to guarantee better functional results.

ACRONYMS AND ABBREVIATIONS: GCT = giant cell tumorHIV = human immunodeficiency virusHBV = hepatitis B virusHCV = hepatitis C virusf-up = follow-upCT = computed tomographyMRI = magnetic resonance imagingPET = positron emission tomographySUV = standardized uptake valueCht (ISG/OS2) = chemotherapyMTX-HD = high-dose methotrexateCDP = cisplatinADM = doxorubicinKMFTR = Kotz Modular Femur-Tibia Reconstruction systemHMRS = Howmedica Modular Resection SystemGMRS = Global Modular Replacement System.

PMID:41064192 | PMC:PMC12499655 | DOI:10.2106/JBJS.ST.24.00011