Research

Cutan Ocul Toxicol. 2025 Jun 4:1-9. doi: 10.1080/15569527.2025.2511721. Online ahead of print.

ABSTRACT

PURPOSE: Primary immune deficiencies (PIDs) can present with a wide range of clinical findings. This review aims to evaluate PIDs in which cutaneous findings are common.

MATERIALS AND METHODS: English literature regarding cutaneous manifestations of primary immunodeficiencies was reviewed using PubMed between January 2005 and March 2023.

RESULTS: Cutaneous findings in PIDs can be broadly classified into two main groups: infectious and non-infectious. The most prevalent skin finding in PIDs is cutaneous infections (bacterial, fungal, and viral), and these infections often manifest as early-onset, recurrent, treatment-resistant, or atypical cases. Eczema is being the most frequent among non-infectious findings. Cutaneous manifestations, such as erythroderma, telangiectasia, granulomatous dermatitis, and autoimmune symptoms like alopecia and vitiligo can also occur.

CONCLUSION: Cutaneous manifestations in PIDs can assist clinicians in making early diagnoses, enabling patients to receive appropriate therapy promptly.

PMID:40465559 | DOI:10.1080/15569527.2025.2511721

Front Biosci (Landmark Ed). 2025 May 20;30(5):27231. doi: 10.31083/FBL27231.

ABSTRACT

Inborn errors of immunity (IEIs) are a group of more than 485 disorders that impair immune development and function with variable reported incidence, severity, and clinical phenotypes. A subset of IEIs blend increased susceptibility to infection, autoimmunity, and malignancy and are known collectively as primary immune regulatory disorders (PIRDs). Programmed cell death, or apoptosis, is crucial for maintaining the balance of lymphocytes. Genetic-level identification of several human inherited diseases with impaired apoptosis has been achieved, such as autoimmune lymphoproliferative syndrome (ALPS), caspase-8 deficiency state (CEDS), X-linked lymphoproliferative syndrome (XLP), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway disorders. The consequences of this disease are manifested by abnormal lymphocyte accumulation, resulting in clinical features such as lymphadenopathy, hepatomegaly, splenomegaly, and an increased risk of lymphoma. Additionally, these disorders are often associated with autoimmune disease, particularly involving blood cells. Understanding the molecular pathogenesis of these conditions has provided critical insights into the signaling pathways that regulate apoptosis and lymphocyte activation, shedding light on mechanisms of immune dysregulation. This review focuses on the intersection between apoptosis, autoimmunity, and lymphoproliferation, discussing how dysregulation contributes to the development of these immune disorders. These conditions are characterized by excessive lymphocyte accumulation, autoimmunity, and/or immunodeficiency. Understanding their molecular pathogenesis has offered new insights into the signaling mechanisms that regulate apoptosis and lymphocyte activation.

PMID:40464495 | DOI:10.31083/FBL27231

Orphanet J Rare Dis. 2025 Jun 3;20(1):270. doi: 10.1186/s13023-025-03749-6.

ABSTRACT

BACKGROUND: The hyper-IgE syndromes (HIES) are a heterogeneous group of inborn errors of immunity-sharing manifestations including increased infection susceptibility, eczema, and raised serum IgE. Pulmonary complications are responsible for high morbidity and mortality rates in patients with HIES. This study examines the progression of pulmonary disease in adult patients with HIES and compares the subsequent findings with existing literature.

METHODS: Ten adult patients with HIES diagnosed at Peking Union Medical College Hospital (PUMCH) from January 2016 to October 2023 were included in this study. Diagnosis was confirmed using the National Institutes of Health (NIH) criteria and whole-exome sequencing. Clinical data on pulmonary disease progression, microbiology, imaging and histology were collected. A systematic literature review was conducted for comparison.

RESULTS: Recurrent pulmonary infections led to significant structural lung damage, with 90.0% (9/10) of patients developing bronchiectasis and pneumatocele. Early infections (0-10 years) were predominantly due to Staphylococcus aureus (80.0%,8/10), while later stages (6-22 years) showed a shift to more complex infections with Aspergillus/fungus (70.0%,7/10), Mycobacterium tuberculosis (50.0%, 5/10), and Pseudomonas aeruginosa (40.0%, 4/10). Imaging revealed extensive bronchiectasis and pneumatocele formation. Histological examinations demonstrated acute inflammation (40%, 2/5), granuloma formation (80%, 4/5), and eosinophilic infiltration (100%, 5/5). Comparatively, our findings are consistent with previous reports that suggest a higher incidence of pulmonary structural damage in patients with the signal transducer and activator of the transcription 3 (STAT3) mutations than in those with other gene variants. However, our cohort showed a faster progression from initial infection to structural damage, highlighting the need for early intervention.

CONCLUSION: The progression of pulmonary disease in HIES patients underscores a critical three-step process: initial recurrent infections, development of structural lung damage, and subsequent reinfections that aggravate the damage. This rapid transition from infection to structural damage, especially in patients with STAT3 mutations, highlights the importance of early and aggressive intervention. Managing reinfections after structural lung damage is essential to prevent further deterioration and to improve long-term outcomes.

PMID:40462219 | DOI:10.1186/s13023-025-03749-6

Pediatr Int. 2025 Jan-Dec;67(1):e70085. doi: 10.1111/ped.70085.

ABSTRACT

PURPOSE: Severe combined immunodeficiency (SCID) is a pediatric emergency, and rapid genetic diagnosis is necessary for proper patient management, leading to successful stem cell transplantation and gene therapy. Ataxia telangiectasia (AT) requires early diagnosis to prevent infectious diseases and early detection of cancer. We aimed to diagnose patients with SCID/AT as quickly as possible and link them to the best treatments via the primary immunodeficiency database in Japan (PIDJ) network.

METHODS: For 111 patients with suspected combined immunodeficiency, including SCID/AT, we analyzed T-cell receptor excision circle (TREC) and sequenced 29 causative genes of SCID, including ATM, by ion semiconductor sequencing using multiplex polymerase chain reaction amplicons. In some cases, DNA extracted from dried blood spots was used for the analysis.

RESULTS: Approximately 70.8% of 0-1-year-old patients and 26.5% of the patients >2 years old with low TREC were diagnosed genetically, including ADA, ATM, IL2RG, IL7R, JAK3, RAG1, RAG2, DCLRE1C, NHEJ1, and LIG4. However, only 6.9% of patients with normal TREC were genetically diagnosed (STIM1 and ATM) in our panel. In Japan, all patients had been genetically diagnosed after infection or other life-threatening conditions, and >80% of patients are linked to appropriate treatment after diagnosis.

CONCLUSIONS: Target gene sequencing, including SCID and AT genes, was useful for the diagnosis of patients with combined immunodeficiency with low TREC and to lead them to prompt treatment and better prognosis.

PMID:40457861 | DOI:10.1111/ped.70085

Front Immunol. 2025 May 19;16:1549768. doi: 10.3389/fimmu.2025.1549768. eCollection 2025.

ABSTRACT

Severe Combined Immunodeficiency (SCID) is a widely underdiagnosed congenital disease that is fatal by 2-years old if left untreated. Most cases of SCID are diagnosed from the prompting of family history while other cases are sporadic and have no indicators for diagnosis besides the onset of debilitating infections. T-cell Receptor Excision Circle Newborn Screening (TREC NBS) offers an accessible way of flagging for SCID and other T-cell lymphopenia; however, the test implementation rate is low, particularly in Asian countries. This review of the literature will explore the significance of TREC NBS for diagnosing SCID with a focus on the potential impact of widespread implementation on infant healthcare in Southeast and East Asian countries including South Korea, Japan, China, Mongolia, Taiwan, Malaysia, Singapore, and Thailand.

PMID:40458401 | PMC:PMC12127307 | DOI:10.3389/fimmu.2025.1549768

J Fish Dis. 2025 Jun 3:e14145. doi: 10.1111/jfd.14145. Online ahead of print.

ABSTRACT

Schizothorax prenanti is an important economic Cyprinidae fish endemic to the upper reaches of the Yangtze River in China. The wild population of S. prenanti continues to decline and has been listed as an endangered fish because of environmental pollution and overfishing. Herein, the skin cell line (SPSK) of S. prenanti was established using the tissue block method to aid in protecting S. prenanti at the cellular level and provide a skin cell line that can be applied in functional genomics and disease aetiology of the spring viraemia of carp virus (SVCV), which is highly infectious in Cyprinidae fish. The SPSK cell line was sub-cultured to more than 30 generations at 24°C in L-15 medium supplemented with 15% fetal bovine serum (FBS). Karyotype analysis further revealed that the chromosome number of SPSK ranged between 140 and 149, with 146 accounting for the highest proportion. Significant fluorescent signals were observed after transfection of SPSK with pEGFP-N1 and Cy3-siRNA, with a 30% and 90% transfection efficiency, respectively. Severe cytopathic effects (CPE) were also observed when SPSK was infected with SVCV, and the SVCV glycoprotein gene was detected by RT-PCR, indicating that SPSK was susceptible to SVCV. To further explore the mechanism of bacterial infection, transcriptome analysis was conducted for LPS treated SPSK cells and 9099 differentially expressed genes were identified. These genes significantly enriched into pathways including the Haematopoietic Cell Lineage and Primary immunodeficiency. Furthermore, seven predominantly expressed epidermal maker genes were identified by transcriptomic data, suggesting that SPSK cells were mainly derived from skin epidermis, composed of epidermal stem cell, Merkel cell, and immune cell. The establishment and characterisation of SPSK revealed its application in functional genomics and aetiology studies, making it a favourable tool for exploring disease control in S. prenanti and recovering fish resources.

PMID:40459177 | DOI:10.1111/jfd.14145

Sci Rep. 2025 Jun 2;15(1):19282. doi: 10.1038/s41598-025-95356-5.

ABSTRACT

This systematic review and meta-analysis aimed to compare the survival outcomes and cytogenetic profile of primary acute lymphoblastic leukemia (p-ALL) and secondary ALL (s-ALL), including antecedent-malignancy ALL (am-ALL) and therapy-related ALL (tr-ALL). The search was performed in PubMed/MEDLINE, Scopus, Web of Science, Embase, and ProQuest databases from January 1, 1990, to July 31, 2023, using the keywords “acute lymphoblastic leukemia” and “second cancer” to identify cohort studies that compared p-ALL and s-ALL in terms of survival outcomes and cytogenetic profile. The risk of bias in the included studies was assessed using the Joanna Briggs Institute (JBI) for Cohort Studies. A total of 7 studies involving 13,542 participants were analyzed. The results revealed an HR of 2.35 (95%CI:1.38-4.01) for overall survival (OS) and 2.06 (95%CI:1.05-4.06) for relapse-free survival (RFS). Subgroup analysis of tr-ALL patients showed a significantly higher HR of 3.40 (95%CI:2.32-4.99) for OS in this subgroup. Furthermore, the meta-analysis indicated an OR of 3.45 and 5.90 for mixed lineage rearrangement (MLL) and hypodiploidy, respectively. The study highlights the need for a better understanding of the survival rates and cytogenetic profile of secondary ALL, particularly tr-ALL, and the importance of personalized treatment strategies for this subtype.

PMID:40456857 | DOI:10.1038/s41598-025-95356-5

Nat Commun. 2025 Jun 2;16(1):5109. doi: 10.1038/s41467-025-60304-4.

ABSTRACT

Ataxia-telangiectasia is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in Ataxia-telangiectasia, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of this disorder is not understood. CD98HC chaperones cystine/glutamate and cationic/neutral amino acid antiporters to the cell membrane, and CD98HC phosphorylation by ATM accelerates membrane localization to acutely increase amino acid transport. Loss of ATM impacts tissues reliant on heterodimeric amino acid transporters relevant to Ataxia-telangiectasia phenotypes, such as endothelial cells (telangiectasia) and pancreatic α-cells (fatty liver and diabetes), with toxic glutamate accumulation. Bypassing the antiporters restores intracellular metabolic balance in ATM-deficient cells and mouse models. These findings provide insight into the long-known benefits of N-acetyl cysteine in Ataxia-telangiectasia cells beyond oxidative stress through removing glutamate excess by producing glutathione.

PMID:40456742 | DOI:10.1038/s41467-025-60304-4

Cureus. 2025 May 1;17(5):e83304. doi: 10.7759/cureus.83304. eCollection 2025 May.

ABSTRACT

Ataxia-telangiectasia (A-T) is a rare neurological disorder that leads to early death due to immunodeficiency, leukemia, and lymphoma. Given the underlying immune dysfunction and predisposition to hematologic cancers, bone marrow transplantation (BMT) or hematopoietic stem cell transplantation (HSCT) has emerged as a potential therapeutic strategy in pediatric patients with A-T. Therefore, longer follow-ups are needed to assess associated risks, side effects, procedures, and eligibility criteria. This systematic review aims to fill this gap by consolidating evidence from different parts of the world on the use of HSCT in pediatric patients diagnosed with A-T. The study used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to search five databases (PubMed, Web of Science, ScienceDirect, Google Scholar, and MEDLINE) for relevant published papers. The review covered studies on both classical and variant forms of A-T. The studies included are those with primary outcomes related to engraftment success, immunological reconstitution, survival rates, transplant-associated toxicity, infection prevalence, cancer management, and neurological progression. Only papers published in English between 2010 and 2024 were eligible for inclusion. Two experienced researchers independently assessed the retrieved papers for inclusion. A structured data collection sheet was used to retrieve relevant information from the selected articles. The risk of bias of the items included prospective and retrospective, cross-sectional, and cohort studies was assessed using the Newcastle Ottawa Quality Assessment Scale. Eight studies were included, comprising various designs including prospective, retrospective, and population-based cohorts. Among these, three studies reported actual use of HSCT or BMT in pediatric patients with A-T, showing immune reconstitution and reduced infections, but limited impact on neurological decline. Reduced-intensity conditioning (RIC) was associated with better survival and fewer complications compared to myeloablative regimens. The remaining studies discussed HSCT theoretically or focused on supportive care, immunological profiles, cancer risk, or nutritional challenges. Overall, outcomes varied, with limited evidence supporting routine use of HSCT in A-T due to associated risks and uncertain long-term benefits. In conclusion, HSCT shows potential in improving immune function and reducing infections in A-T patients. However, it has minimal effect on halting neurological progression. Given the risks and limited long-term data, HSCT is not currently recommended as a standard treatment for A-T.

PMID:40452674 | PMC:PMC12126933 | DOI:10.7759/cureus.83304

Dig Dis Sci. 2025 Jun 2. doi: 10.1007/s10620-025-09106-8. Online ahead of print.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is an umbrella term for numerous primary immunodeficiency syndromes characterized by B-cell, and sometimes T-cell, impairment. While CVID is commonly associated with recurrent sinopulmonary infections, gastrointestinal (GI) disease-often presenting atypically due to immune dysregulation-can significantly the increase morbidity and mortality of those affected.

OBJECTIVES: This review summarizes the diagnostic criteria, epidemiology, and GI manifestations of CVID to increase awareness among general practitioners and gastroenterologists. This review may help facilitate prompt diagnosis and treatment of affected patients.

METHODS: We conducted a narrative review of the literature focusing on the GI manifestations of CVID. This review investigates the GI infections, gastric and bowel diseases, liver involvement, and malignancies associated with this immunodeficiency.

RESULTS: There is no universal definition for CVID, but rather several commonly used diagnostic criteria. Patients with CVID are susceptible to GI infections including those caused by Giardia, norovirus, Salmonella, Campylobacter, and cytomegalovirus. Gastric diseases such as atrophic gastritis and pernicious anemia may present atypically. Bowel involvement may include nodular lymphoid hyperplasia, small intestinal bacterial overgrowth, CVID enteropathy, celiac-like disease, and inflammatory bowel-like colitis. Liver involvement can include autoimmune hepatitis, nodular regenerative hyperplasia, and viral hepatitis. In addition, patients with CVID may have a higher incidence of malignancies such as lymphoma and gastric cancer compared to the general population.

CONCLUSION: CVID is associated with a broad spectrum of infectious and noninfectious GI manifestations that can increase the morbidity and mortality of affected patients. Increased awareness of these complications may facilitate earlier diagnosis and effective management.

PMID:40455348 | DOI:10.1007/s10620-025-09106-8