Research

Front Immunol. 2025 May 9;15:1471168. doi: 10.3389/fimmu.2024.1471168. eCollection 2024.

ABSTRACT

INTRODUCTION: Plasma proteomics analyses were performed to identify novel disease state biomarkers of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) and investigate the biological consequences of specific plasma kallikrein inhibition with lanadelumab.

METHODS: Affinity proteomic analyses were performed using plasma from healthy controls (n=30) and patients with HAE-C1INH before (baseline, n=125) and after 6 months of treatment with lanadelumab (300 mg every 2 weeks, n=112) using the SomaScan platform.

RESULTS: Relative plasma levels for several proteins differed significantly between controls and patients with HAE-C1INH, and between matched baseline and post-treatment samples from patients with HAE-C1INH. As expected, C1 inhibitor and complement C4 were significantly lower (P<1.10e-39 false discovery rate [fdr], P<6.6e-25 fdr, respectively) in HAE-C1INH baseline plasma versus controls. Cleaved high-molecular-weight kininogen, a biomarker of excess kallikrein-kinin system (KKS) activation, was higher in HAE-C1INH baseline plasma versus controls (P<6.7e-6 fdr) and was reduced in HAE-C1INH plasma after lanadelumab treatment. Of 1041 identified proteins that differed significantly (P<0.05) from controls and HAE-C1INH baseline plasma, 120 proteins were no longer different between controls and patients with HAE-C1INH after 6 months of lanadelumab treatment. Canonical pathway and local network analyses of HAE-C1INH plasma proteomics suggest dysregulation in KKS, coagulation, cell adhesion, and connective tissue degradation that approach that of healthy controls following treatment with lanadelumab.

CONCLUSION: Proteomic analyses of plasma from patients with HAE-C1INH before and after treatment with lanadelumab compared with healthy controls confirmed known HAE-C1INH biomarkers and identified additional potential biomarkers of plasma kallikrein dysregulation for further investigation.

PMID:40417315 | PMC:PMC12098075 | DOI:10.3389/fimmu.2024.1471168

Methods Mol Biol. 2025;2933:31-35. doi: 10.1007/978-1-0716-4574-1_5.

ABSTRACT

DNA damage activates cell cycle checkpoints and repairs damages during cell cycle arrest. Radiation-induced S-phase arrest occurs in normal cells, but cells from ataxia telangiectasia (AT) patients present radioresistant DNA synthesis (RDS). AT-derived cells proceed DNA synthesis with DNA damage. Upon detection of radiation-induced DSBs, ATM becomes activated and initiates a signaling cascade that triggers multiple cellular responses aimed to repair the damaged DNA. One of them is the S-phase checkpoint to stop DNA synthesis. Originally, RDS was detected using pulse chase of two radiolabeled thymidines. This chapter introduces modified nonradiolabeled RDS assay using dual labeling of EdU and BrdU and detection of thymidine analogous by specific antibody and Click reaction.

PMID:40418471 | DOI:10.1007/978-1-0716-4574-1_5

Disabil Rehabil. 2025 May 26:1-9. doi: 10.1080/09638288.2025.2508940. Online ahead of print.

ABSTRACT

PURPOSE: Primary immunodeficiency (PID) is a clinically, immunologically, and genetically heterogeneous group of diseases resulting from quantitative and/or qualitative deficiencies of immune system. This study aimed to evaluate adults with primary immunodeficiency (PID) within the scope of the International Classification of Functioning, Disability, and Health (ICF).

MATERIALS AND METHODS: We evaluated 20 adults with PID and 20 healthy adults according to the ICF items. For domain b, exercise capacity, hand-grip strength (HGS), sleep functions, fatigue perception, and body composition; for domain s, posture, and muscle mass were evaluated. Health-related quality of life, activities of daily living, and physical activity were evaluated for domain d. For domain e, supports and relationships, societal attitudes, services, and policies of health, employment, and transportation were determined as barriers.

RESULTS: Exercise capacity, HGS, sleep function, and body composition were significantly impaired, fatigue severity from domain b increased in adult patients with PID compared to healthy controls (p < 0.05). Daily life activities and quality of life from domain d were significantly poorer in patients with PID compared to healthy controls (p < 0.05).

CONCLUSIONS: The evaluation and selecting appropriate outcomes based on ICF-framework will assist health professionals in goal-based rehabilitation plans and better improving functional capacity in adult PID.

PMID:40418537 | DOI:10.1080/09638288.2025.2508940

Lancet Rheumatol. 2025 May 21:S2665-9913(25)00034-7. doi: 10.1016/S2665-9913(25)00034-7. Online ahead of print.

ABSTRACT

BACKGROUND: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently described autoinflammatory disorder with little therapeutic evidence. We compared treatment outcomes of targeted therapies versus prednisolone alone in the largest UK cohort of patients with VEXAS syndrome to date.

METHODS: In this retrospective cohort study, we analysed the outcomes of targeted therapies in patients with VEXAS syndrome in six tertiary referral centres across the UK between July 22, 2014, and Oct 19, 2024. The inclusion criteria were genetically confirmed VEXAS syndrome and receipt of at least one targeted therapy or prednisolone alone. Patients without clinical information at all timepoints after baseline were excluded. Data collection forms were used to record clinical and biochemical data at the following timepoints: time of diagnosis, initiation of treatment, and follow-up at 3 months, 6 months, and 12 months from the initiation of treatment (±28 days). Laboratory parameters, including C-reactive protein (CRP) and haemoglobin, and glucocorticoid doses were collected at each timepoint and compared between timepoints. Primary outcomes were complete response (ie, clinical remission, CRP ≤10 mg/L, and prednisolone ≤10 mg per day) and partial response (ie, clinical remission with ≥50% reductions in both CRP and glucocorticoid dose from baseline) to treatment. Treatment discontinuation and adverse events were documented for each treatment. Due to the high prevalence of cytopenias in VEXAS syndrome, these were only recorded as adverse events when necessitating treatment change. People with lived experience were not involved in the study.

FINDINGS: We analysed 71 targeted therapies in 59 patients with genetically confirmed VEXAS syndrome. Of the 59 patients, 58 (98%) were male and one (2%) was female, with a mean age of 71 years (SD 8), and 27 (46%) had myelodysplastic syndrome. The treatments included tocilizumab (n=19), anakinra (n=13), azacitidine (n=13), baricitinib (n=11), and prednisolone only (n=10). At 6 months, in those who continued therapy, ten (91%) of 11 patients receiving azacitidine showed a response (three [27%] complete responses), as well as did seven (64%) of 11 receiving tocilizumab (four [36%] complete responses), three (100%) of three receiving anakinra (one [33%] complete response), and two (40%) of five receiving baricitinib (no complete responses). Although all patients who tolerated anakinra had a response, the discontinuation rate was high (eight [62%] of 13), mostly due to severe injection-site reactions (n=5). Patients were more likely to respond to azacitidine than to other therapies at 6 months (risk ratio 2·47, 95% CI 1·18-5·20; p=0·018). Absence of fever or thromboembolism at diagnosis was associated with better outcomes. By 6 months, median CRP concentrations had decreased in patients receiving tocilizumab (from 30 mg/L [IQR 13-45] to 4 mg/L [3-37]) or anakinra (from 18 mg/L [11-52] to 2 mg/L [1-28]), whereas azacitidine showed the greatest increase in haemoglobin (from mean concentration 104 g/L [SD 17·5] to 120 g/L [14·4]). 28 (39%) of 71 treatments were discontinued, most commonly due to serious adverse events (12 [17%]) and death (nine [13%]). Infections were most frequent with azacitidine (eight [62%] of 13) and tocilizumab (nine [47%] of 19).

INTERPRETATION: In this UK cohort of patients with VEXAS syndrome, azacitidine and tocilizumab showed superior effectiveness compared with anakinra, baricitinib, and prednisolone only. Treatment selection should consider individual risk factors and tolerability. Prospective studies are needed to confirm optimal treatment strategies and develop standardised protocols.

FUNDING: None.

PMID:40412417 | DOI:10.1016/S2665-9913(25)00034-7

Curr Opin Immunol. 2025 May 24;95:102565. doi: 10.1016/j.coi.2025.102565. Online ahead of print.

ABSTRACT

Autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis are well-defined autoimmune liver diseases, the pathophysiology of which remains enigmatic. While major therapeutic advances have been achieved for many other autoimmune diseases, precision therapy for these diseases has lagged. For example, limited data exist on the use of innovative drugs targeting the immune system, such as monoclonal antibodies that block immune checkpoint, mRNA vaccines, the influence of infections, the microbiome, and drugs on loss of tolerance in liver autoimmunity. The knowledge on recent radiological techniques, on the expanding role of artificial intelligence in medicine, and on the relationship between the pediatric and adult phenotypes also urgently needs to be advanced in liver autoimmunity. Increased patient involvement focusing on individual symptom burden is also crucial for improving long-term quality of treatment. The fourth Swiss Autoimmune Liver Disease Meeting provided a unique interdisciplinary platform for experts and patients to discuss critical gaps. This opinion paper highlights the discussions on unmet needs and potential solutions in autoimmune liver diseases.

PMID:40414140 | DOI:10.1016/j.coi.2025.102565

Immunol Res. 2025 May 24;73(1):86. doi: 10.1007/s12026-025-09642-5.

ABSTRACT

Stromal interaction molecule 1 (STIM1) is a transmembrane protein located in the endoplasmic and sarcoplasmic reticulum, where it plays a crucial role in activating calcium release-activated calcium (CRAC) channels. It functions as a calcium (Ca²⁺) sensor within the endoplasmic reticulum (ER), triggering CRAC channel opening and allowing calcium entry-mechanisms essential for maintaining intracellular calcium homeostasis. Mutations in the STIM1 gene that impair calcium signaling can disrupt both T cell and muscle cell function, leading to combined immunodeficiency and congenital myopathy. Here, we describe a 9-year-old boy with these clinical features, who was found to carry a previously undescribed mutation in the STIM1 gene. The patient presented with recurrent pneumonia, blood-streaked diarrhea, eczema, muscle weakness, and failure to thrive. Whole exome sequencing identified a novel homozygous missense variant in STIM1 (c.584T > C | p.Leu195Pro), considered likely pathogenic. This classification was supported by high Combined Annotation Dependent Depletion (CADD) and Rare Exome Variant Ensemble Learner (REVEL) scores of 29.8 and 0.89, respectively. Homozygosity of the mutation was confirmed using PCR-Sanger sequencing. This case highlights a novel homozygous STIM1 variant in a child with combined immunodeficiency and congenital myopathy. The clinical presentation is consistent with previously reported phenotypes associated with STIM1 deficiency.

PMID:40411647 | DOI:10.1007/s12026-025-09642-5

BMC Rheumatol. 2025 May 23;9(1):57. doi: 10.1186/s41927-025-00508-9.

ABSTRACT

BACKGROUND AND OBJECTIVE: In recent years, many studies have been conducted on the possible link between rheumatologic diseases and inborn errors of immunity. Rheumatologic diseases may occur as manifestations of an underlying immunodeficiency disorder, and may appear before the more-common infectious manifestations more typically seen in immunodeficiency disorders. In this study, we have attempted to study such symptoms and uncover their relationship with inborn errors of immunity.

METHODOLOGY: In this retrospective descriptive-analytical study, 381 cases of IEIs in children that were referred to Mofid Children’s Hospital clinic between 2015 and 2019 were evaluated for eligibility to be enrolled in the study. Of these patients, 20 that had confirmed rheumatologic diagnoses were entered into the study. Patients’ demographic and medical data, including age at disease onset, age at diagnosis and type of diagnosed rheumatologic and immunodeficiency disorders, parental consanguinity rate, and relevant laboratory findings were retrieved for study and analyzed.

RESULTS: Among 20 eligible patients, half of which were female and half were male, the average age at disease onset, average age at diagnosis of the underlying immunodeficiency disease and average age at diagnosis of the rheumatologic disease were 2.98 ± 1.56, 5.26 ± 3.45 and 3.58 ± 2.97, respectively. JIA made up 10 of the observed rheumatic diseases (“the JIA group”); the remaining 10 patients included SLE (3), FMF (2), juvenile dermatomyositis (2), MCTD (1), GPA (1) and reactive arthritis (1) (“the non-JIA group”). As for the underlying immunodeficiency disorders, CID was seen in 8 patients, followed by CVID (5), XLA (4), SIgAD (2) and CGD (1). The average age at onset of the disease and the average age at diagnosis of the rheumatologic disease were significantly lower in the JIA group than in the non-JIA group (p < 0.05).

CONCLUSIONS: A plethora of rheumatologic manifestations may be observed in patients with IEIs; such manifestations should be actively sought out and treated in IEI patients.

CLINICAL TRIAL NUMBER: Not applicable.

PMID:40410798 | DOI:10.1186/s41927-025-00508-9

Cureus. 2025 Apr 22;17(4):e82763. doi: 10.7759/cureus.82763. eCollection 2025 Apr.

ABSTRACT

Introduction Primary central nervous system lymphoma (PCNSL) is a rare type of malignant tumor. Due to the rapidly progressive nature of PCNSL, early diagnosis is important, and imaging plays a key role in this process. In particular, N-isopropyl-p(123I)iodoamphetamine (¹²³I-IMP) single-photon emission computed tomography (SPECT) is useful for PCNSL diagnosis because it shows a high accumulation, which distinguishes the lesion from other brain tumors. Recently, PCNSL has been increasingly observed in immunosuppressed patients, including those who have undergone organ transplantation and those who are receiving treatment for acquired immunodeficiency syndrome. These conditions may alter the tumor microenvironment, thereby potentially influencing ¹²³I-IMP accumulation. The current study aimed to validate how immunosuppression affects the diagnostic imaging of PCNSL using ¹²³I-IMP SPECT. Materials and methods This study included 12 patients diagnosed with PCNSL based on surgical specimens, all of whom underwent early and delayed ¹²³I-IMP SPECT imaging. The patients were divided into the immunosuppressed and non-immunosuppressed groups. The immunosuppressed group consisted of three patients who received steroids or immunosuppressants after kidney transplantation. Seven tumors from the three patients in the immunosuppressed group and nine tumors from the nine patients in the non-immunosuppressed group were compared. Early and delayed SPECT images were obtained, and the regions of interest were defined by fusing SPECT with magnetic resonance imaging. The tumor-to-cerebellum (T/C) ratio was calculated, and statistical analysis was performed using the Mann-Whitney U test. Results The immunosuppressed group had a significantly lower T/C ratio on the early ¹²³I-IMP SPECT images than the non-immunosuppressed group (0.57 ± 0.14 vs 0.83 ± 0.14, p < 0.01). The immunosuppressed group also had a significantly lower accumulation on the delayed images than the non-immunosuppressed group (0.84 ± 0.16 vs. 1.22 ± 0.10, p < 0.001). The T/C ratio showed a statistically significant increase from the early to delayed images in both the immunosuppressed and non-immunosuppressed groups (p < 0.01, p < 0.001). Conclusions The immunosuppressed group had a significantly lower ¹²³I-IMP accumulation in the early and delayed images than the non-immunosuppressed group. Based on this finding, an immunosuppressed state strongly influences the ¹²³I-IMP uptake in PCNSL. Thus, the presence or absence of an immunosuppressed state should be considered when diagnosing PCNSL using ¹²³I-IMP SPECT.

PMID:40406751 | PMC:PMC12096338 | DOI:10.7759/cureus.82763

J Clin Immunol. 2025 May 23;45(1):97. doi: 10.1007/s10875-025-01890-2.

ABSTRACT

PURPOSE: There are few reports of renal involvement in Common Variable Immunodeficiencies (CVID) and, when present, is due to infections, inflammation, or treatments. The aim of this study was evaluating the prevalence of chronic kidney disease (CKD) and to identify CVID-related clinical, laboratory and therapeutic features inducing it.

METHODS: A multicenter observational retrospective study on 367 adult CVID patients from five Italian Referral Centers for Primary Immunodeficiency.

RESULTS: CKD was identified in 23 (6.27%) patients that were older (p < 0.001), had arterial hypertension (p < 0.001), diabetes (p = 0.002), dyslipidemia (p = 0.002), presented different ultrasound abnormalities (p < 0.001) and received predominantly intravenous immunoglobulins (IVIG) (p = 0.016). Regarding CVID infectious and non-infectious manifestations, CKD patients presented a higher frequency of COPD (p = 0.008). In the CKD group, the median absolute count of total lymphocytes (p = 0.015), the percentage of total B (p = 0.028) and transitional B cells (p = 0.008) were lower. By binomial logistic regression analysis adjusted for age, CKD patients tend to develop autoimmune cytopenia, had lower B cells percentage, increased Neutrophil-to-lymphocyte ratio and received more frequently trimethoprim-sulfamethoxazole antibiotic prophylaxis. By multivariate analysis, only autoimmune cytopenia was independently associated with CKD.

CONCLUSION: The prevalence of CKD in CVID is due to aging, age-related comorbidities, disease-related immune dysregulation and inflammation. Our results suggest evaluating renal function in all CVID patients, and mostly in those with a higher “inflammatory” burden.

PMID:40407942 | DOI:10.1007/s10875-025-01890-2

Respir Med Case Rep. 2025 Apr 19;55:102214. doi: 10.1016/j.rmcr.2025.102214. eCollection 2025.

ABSTRACT

We report three cases of bronchiectasis caused by homozygous WFDC2 variants. The ages at diagnosis of bronchiectasis were 18, 24, and 16 years, and all patients had a history of chronic sinusitis since childhood. Despite low nasal nitric oxide levels, the radiologic features resembled those of cystic fibrosis, characterized by bronchiectasis predominantly in the upper lobes. All patients experienced frequent exacerbations and respiratory dysfunction, even with long-term macrolide therapy. Consequently, two of the three patients required lung transplantation. Considering the possibility of founder mutations, WFDC2 variants should be included in diagnostic panels for patients with sinopulmonary disease in Asian populations.

PMID:40401042 | PMC:PMC12093231 | DOI:10.1016/j.rmcr.2025.102214