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Front Immunol. 2025 Apr 30;16:1572194. doi: 10.3389/fimmu.2025.1572194. eCollection 2025.

ABSTRACT

Activated phosphoinositide-3-kinase-delta (PI3Kδ) syndrome (APDS) is an autosomal dominant inborn error of immunity (IEI) characterized by combined immunodeficiency and immune dysregulation with increased risk for lymphoma and other non-lymphoid malignancies. We describe five patients with ovarian malignancies among 110 female APDS patients participating in the European Society for Immunodeficiencies (ESID) registry and identified three additional cases in the literature. These findings document a relevant predisposition to these non-hematological malignancies in APDS patients.

PMID:40370432 | PMC:PMC12075536 | DOI:10.3389/fimmu.2025.1572194

Comb Chem High Throughput Screen. 2025 May 13. doi: 10.2174/0113862073378446250417123724. Online ahead of print.

ABSTRACT

BACKGROUND: The role of kelch like family member 17 (KLHL17) in cervical cancer (CESC) is unclear.

OBJECTIVE: To clarify this uncertainty, our research employed bioinformatics analysis coupled with experimental corroboration.

METHODS: We utilized the Cancer Genome Atlas (TCGA) database to assess the expression of KLHL17 in various cancers, specifically CESC, and to explore its association with clinical characteristics, diagnostic utility, and prognostic significance in CESC. The current investigation delved into the potential regulatory pathways related to KLHL17, examining its connection with the infiltration of immune cells, the expression of immune checkpoint genes, the status of microsatellite instability (MSI), and the efficacy of diverse therapeutic agents in CESC. The research analyzed KLHL17 expression patterns using single-cell sequencing data from CESC samples and investigated the genetic variations of KLHL17 within this context. KLHL17 expression was validated using GSE145372. The presence and levels of KLHL17 in different cell lines were validated through quantitative real-time PCR (qRT-PCR) assays.

RESULTS: KLHL17 exhibited irregular expression profiles across various cancer types, including CESC. Furthermore, increased KLHL17 levels in CESC patients were significantly associated with a lower progression-free survival (PFS) rate (hazard ratio: 1.62; 95% confidence interval: 1.01-2.60, p = 0.044). Moreover, KLHL17 expression emerged as a distinct prognostic indicator for CESC patients (p = 0.031). It has been associated with various biological pathways, such as cytokine-cytokine receptor interaction, primary immunodeficiency, cell adhesion molecules (CAMs), chemokine signaling pathway, steroid hormone biosynthesis, and others. The expression levels of KLHL17 were found to correlate with the presence of immune cells, the expression of immune checkpoint genes, and the status of MSI within CESC. Furthermore, KLHL17 expression exhibited a significant and inverse correlation with XMD15-27, rTRAIL, Paclitaxel, tp4ek, and tp4ek-k6. Furthermore, KLHL17 was found to be significantly positively regulated in CESC cell lines.

CONCLUSION: KLHL17 is a promising prognostic marker and potential therapeutic target in CESC.

PMID:40370232 | DOI:10.2174/0113862073378446250417123724

Br J Anaesth. 2025 May 14:S0007-0912(25)00226-0. doi: 10.1016/j.bja.2025.03.037. Online ahead of print.

ABSTRACT

BACKGROUND: Genetically predicted higher levels of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL1-Ra) might reduce the risk of developing epidural-related maternal fever, a phenomenon that occurs exclusively in women having epidural analgesia in labour. We hypothesised that in women having epidural analgesia, the absence of specific alleles that lower circulating levels of IL1-Ra would be associated with the development of epidural-related maternal fever, administration of intrapartum antibiotics, or both.

METHODS: We prospectively enrolled women ≥18 yr of age receiving epidural analgesia during labour, excluding those with pre-existing fever, antibiotic therapy, or immunodeficiency. Allele scores were constructed from genotyping the C-allele frequency at variants rs6743376 and rs1542176; more copies of each allele independently raise IL-1Ra. The composite primary outcome was maternal intrapartum fever (>38°C) or administration of intrapartum antibiotics after epidural placement. The exposure of interest was the IL1-Ra allele score, comparing 0 (lowest genetically predicted IL-1Ra levels) with ≥1 allele scores. Maternal fever and antibiotic administration were compared in women with 0 or ≥1 allele scores.

RESULTS: Of 624 women genotyped, 155 (24.8%) developed maternal fever or received antibiotics. Fever or antibiotic administration occurred in 19/74 (25.7%) labouring women with an IL-1Ra allele score of 0, compared with 136/550 (24.7%) women with IL-1Ra allele scores ≥1 (odds ratio 1.05, 95% confidence interval 0.60-1.83; P=0.89).

CONCLUSIONS: In women who receive epidural analgesia during labour, genetically predicted (higher) interleukin-1 receptor antagonist levels do not alter the incidence of maternal intrapartum fever or use of intrapartum antibiotics.

CLINICAL TRIAL REGISTRATION: ISRCTN99641204.

PMID:40368685 | DOI:10.1016/j.bja.2025.03.037

J Clin Immunol. 2025 May 13;45(1):92. doi: 10.1007/s10875-025-01880-4.

ABSTRACT

BACKGROUND: Although some reports indicate ocular involvement in Inborn Errors of Immunity (IEI) patients, the characteristics of this association remain unclear. Increased awareness can facilitate early diagnosis and prevention of visual complications.

OBJECTIVE: To determine the prevalence and characterize ophthalmological manifestations in patients with IEI.

METHODS: A systematic literature search was performed across Embase, PubMed, and Lilacs. Observational studies with at least 10 IEI patients exhibiting ophthalmological manifestations were reviewed. A meta-analysis using a random effects model, weighted proportion, and 95% confidence intervals were reported as appropriate.

RESULTS: Sixty-two articles out of the 6,884 studies were included. The pooled prevalence of ocular manifestations in IEI patients was 54% (95%CI = 39-69), with a mean age of 11.1 ± 7.8 years and male predominance. Regarding the type of IEI with ocular involvement, the most frequently affected group was the Combined immunodeficiencies with associated or syndromic features (82%, 95%CI = 66-91), followed by the diseases of immune dysregulation (73%, 95%CI = 27-95), auto-inflammatory disorders (48%, 95%CI = 10-88), and congenital defects of phagocytes (39%, 95%CI = 11-76). Europe had the highest prevalence of patients with ocular manifestations (68%, 95%CI = 32-90). The most common ocular manifestations observed in IEI patients were those affecting ocular mobility, followed by those that involved the anterior segment, posterior segment, eyelids, and adnexal structures.

CONCLUSIONS: These results highlight a significant burden of ocular involvement in IEI patients, mainly during childhood and associated with amblyogenic factors. Therefore, ophthalmologists, pediatricians, and immunologists must be involved in early detection to prevent ocular complications and overall well-being.

PMID:40358744 | DOI:10.1007/s10875-025-01880-4

Hum Genomics. 2025 May 12;19(1):52. doi: 10.1186/s40246-025-00760-7.

ABSTRACT

BACKGROUND: Circular noncoding RNAs (circRNAs) are implicated in many human diseases, but their role in atrial fibrillation (AF) is poorly understood. In this study, we performed bioinformatics analysis of circRNA sequencing data to identify AF-related circRNAs.

METHODS: Left atrial appendage (LAA) samples were obtained from patients with valvular heart disease and were categorised into the sinus rhythm (SR; n = 4) and AF (n = 4) groups. CircRNA sequencing analysis was performed to identify differentially expressed (DE) circRNAs in AF patients. Functional enrichment analysis of DE circRNAs was performed to identify enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways.

RESULTS: We identified 3338 DE circRNAs, including 2147 upregulated and 1191 downregulated circRNAs, in AF patients. A ceRNA network of 16 DE circRNAs, 11 DE miRNAs, and 15 DE mRNAs was constructed. Functional enrichment analyses revealed that the AF-related DE circRNAs were enriched in response to vitamin D, the potassium channel complex, delayed rectifier potassium channel activity, osteoclast differentiation, primary immunodeficiency, endocrine and other factor-regulated calcium reabsorption and other processes. ROC curve analysis identified circRNA_00324, circRNA_17225, circRNA_16305, circRNA_10233, circRNA_05499, circRNA_03183, circRNA_14211, and circRNA_18422 as potential predictive biomarkers for distinguishing AF patients from SR patients, with AUC values of 0.9138, 0.7370, 0.8526, 0.6803, 0.8163, 0.8662, 0.7664, and 0.9320, respectively.

CONCLUSIONS: In this study, we constructed an AF-related ceRNA network and identified eight circRNAs as potential predictive biomarkers of AF.

PMID:40355900 | DOI:10.1186/s40246-025-00760-7

Clin Immunol. 2025 May 10:110513. doi: 10.1016/j.clim.2025.110513. Online ahead of print.

ABSTRACT

Despite advances in genetic testing, Inborn Errors of Immunity (IEI) continue to present a diagnostic challenge, further complicated by genetic variants of uncertain significance (VUS). Therefore, this study evaluated associations of VUS with clinical and immunological characteristics in subjects with potential IEIs. Genes for which VUS were identified were clustered by distinct immune functions. Relationships between gene clusters and clinical and laboratory data were evaluated via SPSS and Python. Both unbiased clustering and manual method classified VUS into six distinct groups based on gene function. Clusters showed association with unique clinical and/or immunological profiles.

PMID:40354868 | DOI:10.1016/j.clim.2025.110513

Allergy. 2025 May 10. doi: 10.1111/all.16580. Online ahead of print.

ABSTRACT

BACKGROUND: Dedicator of cytokinesis protein 8 (DOCK8) is a guanine nucleotide exchange factor highly expressed in, and critical for, the function of various innate and adaptive immune cells. DOCK8 deficiency leads to combined immunodeficiency characterized by susceptibility to infections, autoimmunity, and a severe Th2-type immune response. While dysfunction in various T cell subsets has been implicated in these phenotypes, a comprehensive analysis of the T-cell receptor (TCR) repertoire in these patients has not yet been documented. This study investigates the αβ TCR repertoire in DOCK8-deficient patients to identify features related to disease pathogenesis and explore the potential role of TCR repertoire alterations in disease development.

METHODS: We compared immune repertoire profiles determined by high-throughput TCR sequencing of circulating CD4+ and CD8+ T cells from patients with DOCK8 deficiency (n = 10) to healthy controls (n = 7) and patients with ataxia-telangiectasia (AT) (n = 5).

RESULTS: Different diversity analyses revealed a restricted TRA and TRB repertoire in both CD4+ and CD8+ T cells from DOCK8-deficient patients, with the restriction being more pronounced in CD8+ T cells. Skewed usage of individual variable (V) and joining (J) genes and potentially self-reactive CD8+ T cell clones, as determined by hydrophobicity and cysteine indices, were identified in DOCK8-deficient patients.

CONCLUSION: Our study represents the most comprehensive immune repertoire analysis in DOCK8 deficiency. The identification of a significantly restricted αβ TCR repertoire, along with the detection of potentially autoreactive clones, highlights the crucial role of immune repertoire profiling in elucidating the pathogenesis of DOCK8 deficiency.

PMID:40346988 | DOI:10.1111/all.16580

Immune Netw. 2025 Apr 9;25(2):e18. doi: 10.4110/in.2025.25.e18. eCollection 2025 Apr.

ABSTRACT

The STAT3 is an important regulator in a wide range of different cell types. Human STAT3 variants are associated with several immune dysregulation diseases. The current study investigated the clinical, genetic, and immunobiological data obtained from a family with novel heterozygous STAT3 variants located at p.Y360C of the DNA binding domain. The clinical manifestations of these patients include autoimmunity, immunodeficiency, and postnatal growth defects. Broad STAT3 regulated cells including patient primary immune cells and HEK293 cells harboring the variant were assessed. Remarkably high levels of STAT3-regulated cytokines were detected in the sera of the patients. STAT3 nuclear binding and STAT3 activity were higher in STAT3-transduced HEK293 cells containing the p.Y360C variant when compared to HEK cells expressing wild type (WT) STAT3. Upon cytokine activation, STAT3 variants inhibited nuclear translocation of the WT STAT3 molecule. We also demonstrated that PBMCs from these patients exhibit significantly higher mitochondrial activity compared to that of healthy controls. The exploration of the effects of STAT3 Y360C variants described in our study provides novel insights into the molecular effects of the STAT3 variant and its role in the pathophysiology of STAT3 gain-of-function syndromes.

PMID:40342844 | PMC:PMC12056293 | DOI:10.4110/in.2025.25.e18

Allergol Immunopathol (Madr). 2025 May 1;53(3):41-50. doi: 10.15586/aei.v53i3.1302. eCollection 2025.

ABSTRACT

Primary immunodeficiency diseases (PIDs) show different patterns of airway involvement, particularly bronchiectasis; however, comparative studies of radiologic manifestations in patients with PIDs are scarce. Hence, the aim of this study to investigate radiologic lung findings in adult patients with PIDs and evaluate the possible relationship between clinical and immunologic features and respiratory function in these patients. In this study, the demographic and clinical characteristics, serum immunoglobulins (Ig), lymphocyte subgroups, high-resolution computed tomography (HRCT), and pulmonary function tests (PFTs) of 116 adult patients with PID were evaluated and those with and without abnormal HRCT were compared. The median age was 40 (28-48) years, and there were 51 (44%) females. Abnormal findings were detected in 55.2% of the HRCTs, but the most common findings were bronchiectasis (30.2%), bilateral involvement (73.5%), and lower lobe predominance. The median age and age of diagnosis were higher in those with HRCT findings. The obstructive pattern was the most common found in the PFTs. Forced vital capacity, maximal mid-expiratory flow at 25-75%, immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM), cluster of differentiation (CD)4⁺ T cell, CD4⁺/CD8⁺ ratio, and class-switched memory B (cSMB) cell levels were significantly lower, whereas mortality was higher. Noninfectious pulmonary complications are among the important causes of morbidity and mortality in PID that could result in chronic lung disease despite adequate Ig therapy. Considering the extra radiation dose of HRCT, clinical findings and immunological and PFT parameters accompanying radiological features may be helpful in predicting the diagnosis; it may also be useful in determining additional treatment modalities and reducing mortality.

PMID:40342113 | DOI:10.15586/aei.v53i3.1302

J Scleroderma Relat Disord. 2025 May 4:23971983251333851. doi: 10.1177/23971983251333851. Online ahead of print.

ABSTRACT

BACKGROUND: Hypogammaglobulinemia is a condition that can be related to both primary and secondary immunodeficiencies. While the role of primary immunodeficiency in immune-mediated diseases is well known, its occurrence in systemic sclerosis is not reported.

OBJECTIVES: This study aims to describe the clinical features associated with hypogammaglobulinemia in a cohort of limited cutaneous systemic sclerosis patients.

METHODS: We retrospectively reviewed medical records of systemic sclerosis patients from two Italian referral centres (2010-2024). Included patients had limited cutaneous systemic sclerosis and presented reduced serum concentrations of one or more Ig isotypes (IgG < 700 mg/dL, IgA < 70 mg/dL or IgM < 50 mg/dL) in at least two separate measurements. Patients with secondary causes of hypogammaglobulinemia were excluded. Data collected included demographics, clinical features, Ig levels, infection history and comorbidities.

RESULTS: We identified 30 systemic sclerosis patients (93% female, mean age 62 years) with limited cutaneous involvement and hypogammaglobulinemia. Most patients were positive for anti-centromere antibodies and received periodic intravenous infusions of prostaglandin analogues. No patient received immunosuppressive therapy. Median (interquartile range) serum IgG levels 519.5 (175) mg/dL, median IgA 65.5 (48) mg/dL and median IgM 71.5 (49) mg/dL. Four patients who met the European Society for Immunodeficiencies (ESID) criteria for common variable immunodeficiency experienced recurrent infections and had associated immune-mediated diseases. Five patients had selective IgA deficiency, with frequent immune-mediated comorbidities (thyroiditis, Sjögren’s syndrome, arthritis, psoriasis). The other patients exhibited mild IgG deficiency without a significant infectious history.

CONCLUSIONS: This is the first study describing a cohort of patients with limited cutaneous systemic sclerosis and hypogammaglobulinemia. Our population presented a high prevalence of immune-mediated comorbidities but low infection rates. Further research is needed to explore the underlying mechanisms and clinical significance of hypogammaglobulinemia in these patients.

PMID:40337344 | PMC:PMC12052914 | DOI:10.1177/23971983251333851