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Front Immunol. 2025 Jul 22;16:1598491. doi: 10.3389/fimmu.2025.1598491. eCollection 2025.

ABSTRACT

Subcutaneous immunoglobulin (SCIG) preparations are widely used in patients with inborn errors of immunity (IEI), with proven efficacy and good tolerance. We assessed treatment efficacy, safety, and quality of life in a large cohort of IEI patients who switched from intravenous immunoglobulin (IVIG) to SCIG. Our observational study included 200 patients aged 1-65 years with IEI. SCIG Cutaquig (16.5%) was administered every 7-10 days for at least 12 months via the rapid push method. We assessed the rate of infection, immunoglobulin G (IgG) concentration, adverse events, and quality of life. A total of 8,787 SCIG doses were administered during the study. The rate of infections (per person/month) during SCIG treatment was 0.05, which was significantly lower compared to 0.19 during the IVIG period (p<0.001). The median trough IgG was 6.9 g/L on IVIG, compared to 9.0 g/L during the first six months, and 9.2 g/L during the next six months on SCIG. Systemic reactions occurred in 12.4% of the IVIG infusions and 1.9% of the SCIG infusions. The total scores on quality of life summary assessments of physical and mental health were higher on SCIG therapy compared with IVIG (p<0.001). At the end of the study, 85.6% of the patients chose to remain on SCIG. Our data suggest that SCIG infusion via the rapid push method is effective, well tolerated, and feasible in large groups of IEI patients, including those in large countries such as Russia.

PMID:40766319 | PMC:PMC12321879 | DOI:10.3389/fimmu.2025.1598491

Front Immunol. 2025 Jul 22;16:1631448. doi: 10.3389/fimmu.2025.1631448. eCollection 2025.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) is a genetic disorder characterized by episodic subcutaneous and submucosal swelling. Patient-reported outcome measures (PROMs) are recommended for routine clinical assessment by international guidelines and are used as secondary outcome measures in pivotal clinical trials for novel investigational drugs. The Angioedema Control Test (AECT) and Hereditary Angioedema Activity Score (HAE-AS) are validated tools designed to aid in HAE patient assessment, but the extent to which they measure different disease outcomes is unclear. The aim of this study was to examine how these measures correlate and inform clinical practice.

METHODS: We conducted a retrospective study of patients with HAE types 1 and 2 at the Edmonton Angioedema Center of Reference and Excellence. AECT and HAE-AS scores were obtained from patient-completed questionnaires during routine visits. Multiple linear regression was used to examine the association between HAE-AS and AECT scores with age, sex, and long-term prophylaxis (LTP) status as predictors. Receiver operating characteristic (ROC) analysis was used to determine the optimal HAE-AS score cutoff that predicts poor disease control as determined by the AECT.

RESULTS: There were 25 participants included with a mean age of 39.4 years (SD = 13.7), 72% of whom were female. Most had HAE Type 1 (76%) and 52% were receiving LTP. SC C1-inhibitor therapy was the most common LTP (36%). Most had well managed disease with a median AECT score of 11.88 (range: 5-16) and HAE-AS of 5.84 (range: 0-13). A statistically significant but weak negative correlation was found between AECT and HAE-AS (β=-0.67, p=0.002). ROC analysis showed that an HAE-AS score >5 had a sensitivity of 100% and specificity of 61% for poor disease control.

CONCLUSIONS: The AECT and HAE-AS instruments are weakly correlated, indicating that they provide related but distinct information to the practicing clinician. Using both AECT and HAE-AS in clinical practice can thus provide a more comprehensive patient evaluation.

PMID:40766317 | PMC:PMC12321560 | DOI:10.3389/fimmu.2025.1631448

Zhonghua Jie He He Hu Xi Za Zhi. 2025 Aug 12;48(8):719-725. doi: 10.3760/cma.j.cn112147-20250117-00036.

ABSTRACT

Objective: To evaluate the diagnostic value of whole exome sequencing (WES) for difficult and complicated pulmonary diseases. Methods: A retrospective analysis was conducted on patients with difficult and complicated pulmonary diseases who underwent WES at Peaking Union Medical College Hospital from May 2021 to August 2024. Demographic information, clinical data, and WES results were collected and systematically analyzed. Results: A total of 24 patients were included, comprising 14 males (58.33%) and 10 females (41.67%). The median age of the patients was 28 years (range: 14-64 years). WES identified nine pathogenic or likely pathogenic genetic variants associated with six genes, leading to a definitive diagnosis in seven patients (diagnostic rate: 29.17%). Among the diagnosed cases, primary immunodeficiency diseases accounted for the largest proportion. WES also showed certain diagnostic value for certain rare diseases with pulmonary involvement, such as vascular Ehlers-Danlos syndrome (vEDS). Conclusion: WES is recommended because it can effectively improve the diagnostic rate for patients with difficult and complicated pulmonary diseases, particularly early-onset cases and those involving multisystem or recurrent infections.

PMID:40764132 | DOI:10.3760/cma.j.cn112147-20250117-00036

Orphanet J Rare Dis. 2025 Aug 4;20(1):397. doi: 10.1186/s13023-025-03919-6.

ABSTRACT

BACKGROUND: Ataxia telangiectasia (A-T) is a rare genetic and progressive condition, primarily affecting the neurological, immunological, and pulmonary systems. In the absence of a cure, people living with A-T require co-ordinated multidisciplinary care to manage their complex needs. This often leads to families working with a range of different professionals and feeling burdened by the amount of information and coordination of care that they manage. With the aim to inform the co-production of a family-owned healthcare pack to promote person-centered care and self-management, this study explored the views of children with A-T and parents of children and young people with A-T about the utility, acceptability, design, and content of this pack.

RESULTS: A total of two children and eight parents participated in one pilot interview and three focus groups. Using the Framework Method of analysis, three themes were generated offering an insight to the range of participants’ views. The first theme, ‘accessing, managing, organising, and sharing information with others’, broadly highlighted the need for a pack as a valuable resource in the absence of coordinated care and a centralised system of record keeping and information sharing. The second theme, ‘pack content’, suggested that the pack may serve the dual purpose of storing and retrieving information and helping to communicate and work with other professionals. The third theme, ‘design features’, investigated the design of the pack and the differences in the views of children who wanted the pack to look like a magazine style booklet, and the parents who preferred an electronic pack or an app.

CONCLUSION: This study is an important contribution to the current understanding of the experiences of care and management of A-T from the point of view of children with A-T and their parents. Families with a child with A-T struggle with communication and information sharing across and between different professionals. My A-T Pack is a step towards providing families a viable resource for effective record keeping, symptoms management, and information sharing with relevant professionals involved in the care and management of their child’s condition.

PMID:40759969 | DOI:10.1186/s13023-025-03919-6

J Clin Immunol. 2025 Aug 2;45(1):121. doi: 10.1007/s10875-025-01917-8.

ABSTRACT

The interleukin-2 receptor γ (IL-2Rγ, or γc) is a crucial component of several cytokine receptor complexes. Deficiencies in γc lead to X-linked severe combined immunodeficiency (X-SCID), characterized by recurrent infections due to the absence or dysfunction of T and NK cells, and nonfunctional B cells. Missense variants in the γc extracellular region are linked to atypical X-SCID with normal counts of T, B, and NK cells and less severe symptoms, yet the underlying cellular and molecular mechanisms are not well understood. This study describes a case of atypical X-SCID with a missense variant (c.420 A > T, p.R140S) in the γc extracellular domain, associated with recurrent bacterial, fungal, and viral infections. We found that the R140S variant leads to reduced surface expression and variably affects cytokine receptor signaling. Specifically, STAT5 phosphorylation and proliferation in CD4⁺ T and CD8⁺ T cells are impaired in response to IL-7, a cytokine essential for T cell survival, proliferation and function. Notably, γc^R140S predominantly localizes to the endoplasmic reticulum, in contrast to WT γc, which is found in acidic compartments. Despite this mislocalization, γc^R140S does not trigger unfolded protein responses, and its protein stability and degradation pathways remain unaffected. Nevertheless, cells expressing high levels of γc^R140S exhibited a competitive disadvantage in culture compared to those expressing WT γc, resulting in the enrichment of cells expressing lower levels of γc^R140S. These findings extend our understanding of how mutations in the extracellular domain of γc can lead to reduced protein expression and influence the pathophysiology of atypical X-SCID.

PMID:40751765 | DOI:10.1007/s10875-025-01917-8

J Clin Immunol. 2025 Aug 1;45(1):119. doi: 10.1007/s10875-025-01921-y.

ABSTRACT

BACKGROUND AND OBJECTIVES: Germline pathogenic variants in the mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) encodes a caspase-like protease that plays a crucial role in the caspase recruitment domain (CARD)-B-cell lymphoma 10 (BCL10)-MALT1 (CBM) complex. This complex mediates the activation of nuclear factor-kB (NF-kB) pathway and are associated with diverse human diseases including combine immunodeficiency (CID), lymphoproliferation and others. This study aimed to determine the underlying cause of immune deficiency and immune dysregulation in a patient presented with recurrent respiratory infections, aphthous ulcers, dermatitis, chronic diarrhea, failure to thrive and early death.

METHODS: Clinical and laboratory records were reviewed. Patients underwent next-generation sequencing (NGS), and analysis of genomic DNA was performed on the patient and her parents. Lymphocyte subsets, MALT1 expression and NF-kB signaling was evaluated by flow cytometry, RT-PCR and immunoblotting.

RESULTS: The patient carried a novel pathogenic biallelic loss-of-function variant in MALT1 (c.1411G > A; p.D471N) located in the caspase-like domain, leading to severely reduced MALT1 protein expression. Impaired CBM-mediated NF-κB activation was confirmed by reduced phosphorylation of the p65 subunit, resulting in deficient production of IL-2 and TNF-α. This functional defect caused lower Tfr and Treg cells, a normal proportion of Tfh cells, with higher expression of activation markers PD-1 and ICOS. The patient displayed low NK cell and B cell counts, together with a developmental block at the transitional B cell stage. Additionally, the proportion of marginal zone-like B cells (MZB-like) was markedly decreased, indicating impaired B cell differentiation.

CONCLUSIONS: Human MALT1 deficiency causes profound CID by impairing CBM-mediated NF-kB signaling and MALT1-paracaspase activity. Consistent with the reported variants located in the caspase-like domain, our patient presented with an inflammatory phenotype, supporting the notion that the MALT1 D471N mutation phenocopies a partial loss of both MALT1 scaffolding function and paracaspase activity. Prompt hematopoietic stem cell transplantation (HSCT) is highly recommended as an effective therapy for MALT1 deficiency.

PMID:40748513 | DOI:10.1007/s10875-025-01921-y

J Clin Immunol. 2025 Aug 1;45(1):120. doi: 10.1007/s10875-025-01906-x.

ABSTRACT

PURPOSE: Baraitser-Winter syndrome type 1 (BRWS1) is a rare disorder characterized by intellectual disability, short stature, facial dysmorphism, cortical malformations, macrothrombocytopenia, and recurrent infections. BRWS1 is caused by loss-of-function variants in ACTB, leading to β-actin deficiency. Given the essential role of the actin cytoskeleton in T-cell activation, the immunological consequences of ACTB mutations remain unexplored. Here, we characterize immune dysfunction associated with a novel ACTB variant in a patient with BRWS1.

METHODS: Whole-exome sequencing identified a heterozygous ACTB p.Gln360ProfsTer4 variant in a patient with BRWS1 and combined immunodeficiency. Functional studies were performed in HEK293T cells transfected with wild-type and mutant ACTB constructs. Patient-derived T cells were analyzed for immunological synapse formation, cytokine production, activation, and proliferation. The therapeutic effects of exogenous IL-2 and dupilumab were evaluated.

RESULTS: The mutant β-actin protein was rapidly degraded and exerted a dominant-negative effect on wild-type β-actin, thereby disrupting cytoskeletal integrity. Patient-derived T cells demonstrated defective immunological synapse formation, reduced intra-synaptic IL-2 levels, and impaired activation and proliferation. Supplementation with exogenous IL-2 partially restored T-cell function in vitro. Notably, dupilumab treatment led to significant clinical and immunological improvement, suggesting a role in restoring immune regulation.

CONCLUSION: BRWS1 represents a novel primary immune regulatory disorder. Our findings highlight actinopathy-driven immunodeficiency as a target for therapeutic intervention, with broader implications for cytoskeletal disorders.

PMID:40748410 | DOI:10.1007/s10875-025-01906-x

Virchows Arch. 2025 Aug 1. doi: 10.1007/s00428-025-04189-0. Online ahead of print.

ABSTRACT

Session 2 of the 2024 European Association for Haematopathology/Society for Hematopathology lymphoma workshop was dedicated to atypical lymphoproliferations in association with germline genetic variants. The first group of cases were lymphoproliferations occurring in the context of primary immunodeficiencies (PID), a heterogeneous group of diseases with increasing incidence and number of different diseases due to better recognition. The workshop contained a spectrum of different PIDs and associated lymphoproliferations with autoimmune lymphoproliferative syndrome, activated phosphoinositide 3-kinase delta syndrome, ataxia-telangiectasia and common variable immune deficiency being the most common. Both children and adults were affected, and the diagnosis of an underlying PID often required a high index of suspicion and correlation with clinical presentation and immunological/ infectious workup. Recognition of a PID allows specific treatment and can influence the interpretation of lymphoproliferations occurring in this context. The spectrum of lymphoproliferations ranged from reactive to overt lymphoma, both EBV-positive and -negative. In a subset of cases, it was very difficult or impossible to establish the boundary between reactive and neoplastic in the context of a PID. The second group represented a heterogeneous group of lymphoproliferations in the context of mutations in germline haematopoietic malignancy risk genes, without associated immunodeficiency. It was often difficult to determine if the genetic defect and the lymphoproliferation were causally related or coincidental, especially if the patient was also treated for non-lymphoid conditions. This is a rapidly evolving field in which future studies are expected to shed more light on the relationship between germline mutations and lymphoid malignancy.

PMID:40748381 | DOI:10.1007/s00428-025-04189-0

J Pediatr Endocrinol Metab. 2025 Aug 1. doi: 10.1515/jpem-2025-0275. Online ahead of print.

ABSTRACT

OBJECTIVES: Glycerol kinase deficiency (GKD) is a rare X-linked metabolic disorder caused by pathogenic variants in the GK gene. It can be present in either isolated or complex forms and often mimics primary hyperlipidemia, leading to diagnostic challenges and unnecessary treatment. This study aims to highlight the phenotypic variability and diagnostic features of GKD through a case series.

CASE PRESENTATION: We describe three pediatric patients diagnosed with GKD. Two siblings with isolated GKD presented with persistent, asymptomatic hypertriglyceridemia, confirmed by glyceroluria and genetic testing revealing a hemizygous c.213_214delAT (p.Cys72Ter) mutation. The third patient, diagnosed with complex GKD, presented in infancy with multisystem involvement, including immunodeficiency, hypotonia, splenic abscesses, and elevated and creatine kinase levels. Genetic analysis revealed a 6.9 Mb contiguous deletion spanning Xp21.2-Xp11.4. In all cases, elevated triglyceride levels were unresponsive to therapy, and serum samples lacked lipemic appearance. Lipid-lowering treatments were discontinued following diagnosis, with no adverse outcomes.

CONCLUSIONS: This case series underscores the clinical and genetic heterogeneity of GKD. Urinary glycerol analysis and the absence of serum lipemia are key diagnostic clues. Early recognition is essential to prevent misdiagnosis and guide appropriate management, particularly in treatment-resistant hypertriglyceridemia.

PMID:40741920 | DOI:10.1515/jpem-2025-0275

Front Cell Infect Microbiol. 2025 Jul 16;15:1615929. doi: 10.3389/fcimb.2025.1615929. eCollection 2025.

ABSTRACT

Caspase recruitment domain containing protein 9 (CARD9) deficiency is an autosomal-recessive primary immunodeficiency disorder, undermines the body’s capacity to combat fungal infections. In recent years, the number of reported cases of fungal infections associated with CARD9 deficiency has been increasing. This study undertook a systematic review of case reports, incorporating 89 patients with CARD9 deficiency complicated by fungal infections. The findings demonstrated that the patient population predominantly consisted of young and middle-aged individuals (33.43 ± 19.12 years, range: 1-91), and the majority (52 patients, 58.43%) developed the disease during childhood or adolescence. Significant geographical variations were observed in the distribution of gene mutations. Specifically, the c.820dupG mutation was predominantly found in East Asia, while the c.865C>T mutation was primarily found North Africa. Regarding the clinical manifestations, the most frequently affected sites were the skin, central nervous system, and lymph nodes, and the principal fungal pathogens identified were Trichophyton and Candida. Correlation analysis indicated that c.883C>T increased the likelihood of Candida infection (p=0.008, OR=10.421, 95% CI 1.849-58.748), c.865C>T increased the probability of Trichophyton infection (p=0.038, OR=5.760, 95% CI 1.098-30.217) and dematiaceous fungi infection (p=0.005, OR=9.653, 95% CI 2.019-46.153). According to the types of mutations, nonsense mutation increased the risk of dematiaceous fungi infection (p=0.014, OR=6.212, 95% CI 1.453-26.556). Notably, a proportion of patients succumbed to the disease, and this was predominantly associated with infections of the central nervous system, blood system, and viscera. This underscores the importance of adequate antifungal therapy and long-term follow-up for patients with CARD9 deficiency-related fungal infections.

PMID:40740345 | PMC:PMC12307477 | DOI:10.3389/fcimb.2025.1615929