Research

Expert Rev Clin Immunol. 2026 Feb 16. doi: 10.1080/1744666X.2026.2633137. Online ahead of print.

ABSTRACT

INTRODUCTION: Inborn errors of immunity (IEIs), also known as primary immunodeficiency diseases (PIDs) since 2017 Inborn Errors of Immunity Committee classification, comprise a heterogeneous group of genetic disorders resulting in impaired immune development and function. Malignancy is a major challenge in IEIs, particularly in those with defects in DNA repair, tumor suppression, immune surveillance, or chronic inflammatory control, highlighting the close interplay between immune dysfunction and oncogenesis.

AREAS COVERED: Hematologic malignancies, especially non-Hodgkin lymphomas, predominate in IEIs, though epithelial tumors also occur and present at younger ages with poorer outcomes. Both intrinsic factors – such as genomic instability and defective lymphocyte maturation – and extrinsic factors, including chronic inflammation, oncogenic viral infections, and iatrogenic exposures, contribute to cancer development. Subtypes such as ataxia-telangiectasia, Nijmegen breakage syndrome, Wiskott – Aldrich syndrome, and common variable immunodeficiency show particularly high malignancy rates. Defects in specific immune pathways, including CD40L or IL-10 receptor signaling, may predispose to organ-specific or virus-driven cancers.

EXPERT OPINION: Although hematopoietic stem cell transplantation remains curative for select IEIs, post-transplant malignancy risk persists. A deeper understanding of shared molecular pathways linking immunodeficiency and cancer is essential to refine early diagnosis, risk stratification, and targeted management in this vulnerable population.

PMID:41693687 | DOI:10.1080/1744666X.2026.2633137

Rare Dis Orphan Drug J. 2025 Oct 14;4(4):rdodj.2025.42. doi: 10.20517/rdodj.2025.42.

ABSTRACT

Inborn errors of immunity (IEIs), also known as primary immunodeficiencies, are a group of rare inherited disorders that affect the immune system. They result in severe, opportunistic infections, severe autoimmune manifestations and a predisposition to malignancy. The only curative treatment for many years has been allogenic haematopoietic stem cell transplantation (alloHSCT). However, this requires the availability of a suitable donor and has risks of morbidity and mortality. Autologous gene therapy (GT) abrogates the immunological complications of alloHSCT and uses the patient’s own cells, removing the need for a donor. Preclinical proof-of-concept and clinical trials in humans have demonstrated that GT is safe and effective and can be used to correct a variety of IEIs. In this review, we outline the progress in developing GT for IEIs over the last four decades. We describe the gene editing technologies available to correct IEIs and their current applications. We also examine advances in GT development, the challenges to its application, and discuss future developments in the field, including emerging in vivo approaches.

PMID:41693912 | PMC:PMC7618722 | DOI:10.20517/rdodj.2025.42

JPGN Rep. 2025 Oct 23;7(1):11-13. doi: 10.1002/jpr3.70099. eCollection 2026 Feb.

ABSTRACT

Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare autosomal recessive primary immunodeficiency. Patients with DOCK8 deficiency typically present at early age with allergic manifestations, cutaneous and respiratory infections, raised immunoglobulin E, and they have an increased risk of developing malignancies. Hematopoetic stem cell transplantation (HSCT) is the only curative treatment for DOCK8 deficiency. We present a female paediatric patient with DOCK8 deficiency who was assessed for HSCT, but underwent liver transplantation fist in view of decompensated liver disease. The patient, unfortunately, succumbed secondary to infectious complications in the post-op period.

PMID:41695074 | PMC:PMC12894047 | DOI:10.1002/jpr3.70099

Shock. 2025 Dec 11. doi: 10.1097/SHK.0000000000002768. Online ahead of print.

ABSTRACT

BACKGROUND: Sepsis is a persistent systemic inflammatory disease involving multiple organ failure caused by a dysregulated immune response to infection. As primary effector cells in innate immunity, neutrophils significantly contribute to combating infections and mediating inflammatory responses. The aim of this study was to evaluate the prognostic significance of neutrophil-related genes (NRGs) in sepsis and their relationship with the immune microenvironment.

METHODS: This study was drawing on transcriptomic data and clinical characterization of sepsis patients from the GEO database. Sepsis prognostic genes were discovered through a combination of differential analysis, weighted gene co-expression network analysis (WGCNA), and univariate cox regression analysis. Molecular subtypes of sepsis were identified by consensus clustering methods, survival differences between subtypes were compared and gene enrichment analysis was performed. Further univariate cox regression analysis and LASSO combined were performed to identify sepsis feature genes. Utilizing multivariate cox regression analysis, a prognostic model was developed, and its predictive capability was subsequently examined through receiver operating characteristic (ROC) curve and Kaplan-Meier (K-M) survival analyses. Subsequently, immune cell infiltration and gene enrichment were assessed in the various risk groups.

RESULTS: This study identified the presence of two molecular subtypes in sepsis, with Cluster1 patients having significantly better survival than Cluster2. The prognostic model based on NRGs (RCBTB2, KRT23, KLF9, GIMAP4 and CD84) in this study significantly differentiated the survival prognosis of high risk and low risk patients. The low risk patient group showed significant enrichment in immune related pathways (T cell receptor signaling and primary immunodeficiency), while the high risk group primarily exhibited significant enrichment in metabolism related pathways (glycine serine and threonine metabolism).

CONCLUSION: Risk models constructed on the basis of NRGs are effective in predicting survival outcomes and immune profiles of sepsis patients, providing a new perspective on the link between NRGs and sepsis.

PMID:41697141 | DOI:10.1097/SHK.0000000000002768

J Clin Immunol. 2026 Feb 14. doi: 10.1007/s10875-026-01993-4. Online ahead of print.

NO ABSTRACT

PMID:41688586 | DOI:10.1007/s10875-026-01993-4

Transpl Infect Dis. 2026 Feb 13:e70155. doi: 10.1111/tid.70155. Online ahead of print.

ABSTRACT

BACKGROUND: Infection is a common complication following umbilical cord blood transplantation (UCBT), yet comprehensive data on pediatric patients with inborn errors of immunity (IEIs) in China are scarce. This study aimed to characterize infection profiles and their prognostic implications in this population.

METHODS: We retrospectively analyzed 165 IEIs patients undergoing UCBT between January 2015 and June 2020. The post-transplantation period was divided into early (≤ 30 days) and middle (31-100 days) stages.

RESULTS: Within 100 days, 115 patients (69.7%) experienced 217 infection episodes. Engraftment failure was an independent predictor of infection risk within 100 days (OR = 2.97, p = 0.04). Low pre-transplantation IgM levels and graft-versus-host disease (GVHD) prophylaxis with calcineurin inhibitors (CNIs) plus mycophenolate mofetil (MMF) increased early-stage infection risks (p < 0.05). Infections at the middle stage were correlated with Grade II-IV acute GVHD (p = 0.03). Bloodstream infections (BSIs) were linked to CNIs combined with MMF and lower total nucleated cell counts in cord blood (p < 0.05). Early-stage infected group exhibited significantly poorer survival versus uninfected and middle-stage groups (p < 0.001). Patients without bacterial infections had higher survival rates than those with carbapenem-resistant or non-resistant infections (p < 0.05). BSIs were associated with poor prognosis (p < 0.05), while cytomegalovirus infection showed no significant survival impact (p = 0.05).

CONCLUSIONS: Infections are highly prevalent in IEIs children post-UCBT, with early-stage events and BSI portending poorer outcomes. These findings advocate for risk-stratified surveillance and preemptive strategies in high-risk subgroups.

PMID:41688817 | DOI:10.1111/tid.70155

Clin Genet. 2026 Feb 13. doi: 10.1111/cge.70147. Online ahead of print.

ABSTRACT

Pathogenic variants in GINS1 are believed to cause a primary combined immunodeficiency and growth retardation syndrome with natural killer cell deficiency and chronic neutropenia. To date, however, very few cases have been reported. Thus, the role of GINS1 in disease, as well as the spectrum of variants and their associated phenotype, remains unclear. We present a 2-year-old female with growth retardation, chronic neutropenia, distinctive facial features, and glaucoma. Exome sequencing revealed two likely pathogenic variants in GINS1, c.-48C>G p.? and c.247C>T p.Arg83Cys, conferring a diagnosis of GINS1 deficiency. She has overlapping features with the previously reported individuals, cementing growth retardation, neutropenia, and natural killer cell deficiency as core features. We additionally present a review of all nine individuals reported to date. We highlight that our proband, unlike the others, has no history of infections, and that glaucoma has now been observed in multiple unrelated individuals, pointing toward possible phenotypic expansion. Efforts to identify affected individuals, including those with different variants and phenotypes, are needed to understand ways in which GINS1 may be implicated in disease and the phenotypic spectrum of this ultrarare inborn error of immunity.

PMID:41689265 | DOI:10.1111/cge.70147

Orphanet J Rare Dis. 2026 Feb 12;21(1):55. doi: 10.1186/s13023-025-04123-2.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE), a rare autosomal dominant disorder characterized by recurrent, potentially life-threatening attacks of cutaneous or submucosal swelling, affects patients’ everyday activities and psychological well-being. Although caregivers are instrumental in helping patients cope with HAE, its impact on the caregivers’ quality of life is poorly documented. Using web-based surveys (July 2022‒February 2023), this international study (Argentina, Brazil, Colombia, Croatia, Denmark, Germany, Hungary, Ireland, Norway, Poland, Portugal, Romania, and Sweden) assessed the humanistic and psychosocial burden of caregivers (≥ 18 years old) of pediatric (< 18 years) and adult (≥ 18 years) patients with diagnosed HAE.

RESULTS: In total, 120 caregivers completed the surveys: 54 caregivers of pediatric patients (CoPs; mean age 40.6 years; 79.6% female) and 66 caregivers of adult patients (CoAs; mean age 42.7 years; 48.5% female). CoPs and CoAs reported 5.6 and 13.1 HAE attacks (mean) in the past 6 months for individuals receiving their care, respectively. CoPs provided care for 23.5 days (mean) per month on average; in the past 4 weeks, CoPs missed (mean) 2.6 days (mean) of work, while the children missed 3.9 days (mean) of school. CoPs cited a lack of understanding of their caregiving duties from schools (20.4%), employers/coworkers (16.7%), family (13.0%), friends (13.0%), and partner/spouse (13.0%). CoPs reported impacts on their work (37.0%), sleep (37.0%), and household chores (31.5%), and restricted time with family (29.6%), spouses/partners (27.8%), and friends (24.1%). Emotional impacts on the CoPs included worry about the child’s health (90.7%) and future (68.5%); CoPs themselves reported having sleep problems (24.1%), migraine (22.2%), gastrointestinal disorders (22.2%), and anxiety (20.4%). CoAs reported impacts on their work (28.8%), sleep (28.8%), and recreational activities (27.3%), leading to missing time of work (mean 0.94 days in past 4 weeks). Emotional impacts on the CoAs included worry about the health of individual they provide care for (92.4%) and future (40.9%); CoAs themselves reported having anxiety (13.6%), migraines (13.6%), and sleep problems (12.1%).

CONCLUSION: Results of this caregiver survey revealed that the caregiver role in HAE is time-demanding and adversely impacts various aspects of the caregiver’s life, particularly their emotional wellbeing.

PMID:41680909 | DOI:10.1186/s13023-025-04123-2

Int J Mol Sci. 2026 Feb 3;27(3):1518. doi: 10.3390/ijms27031518.

ABSTRACT

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency or inborn error of immunity (IEI) encountered in clinical practice. Characterized by a remarkably broad clinical spectrum, CVID presents with phenotypes spanning from “infection only” to significant non-infectious complications. The frequent overlap between these classifications underscores that their distinction is more accurately viewed as a continuous spectrum, rather than a binary categorization. CVID-associated liver disease is a significant source of morbidity, yet often poses diagnostic challenges due to its insidious and clinically silent nature, typically becoming apparent only upon the development of complications. Manifestations range from abnormal liver tests to irreversible organ damage, with reports including granulomas, autoimmune hepatitis, fibrosis, and porto-sinusoidal vascular disorder (PSVD). Regenerative nodular hyperplasia (RNH), commonly associated with PSVD, is a frequent histopathological finding. Management requires a multidisciplinary approach, including cause-directed immunosuppression and supportive treatment for non-cirrhotic portal hypertension. Despite significant advances in comprehending CVID-associated liver involvement, substantial gaps persist concerning its pathogenesis, its optimal management, and the correlation between histological findings and clinical outcomes. A heightened awareness of CVID-associated liver disease is paramount for multidisciplinary teams across IEI centers. Furthermore, given its prevalence, its insidious clinical phenotype until advanced complications, and the significant diagnostic delay and underdiagnosis, such awareness is critical across a broader range of medical specialties. In this paper, we aim to consolidate current knowledge regarding CVID-related liver disease, examining its clinical presentation, recent genetic and pathogenetic advancements along with current diagnostic methodologies, and therapeutic strategies.

PMID:41683939 | DOI:10.3390/ijms27031518

Front Immunol. 2026 Jan 28;17:1723142. doi: 10.3389/fimmu.2026.1723142. eCollection 2026.

ABSTRACT

RAC2-related immunodeficiency is a rare inborn error of immunity with a broad clinical spectrum ranging from neonatal severe combined immunodeficiency to atypical combined immunodeficiency diagnosed later in life. We describe two unrelated French-Canadian patients carrying a rare, homozygous RAC2 variant (c.202C>T; p.R68W), both presenting with combined immunodeficiency. The first patient developed recurrent bacterial respiratory infections and early bronchiectasis that initially responded to immunoglobulin replacement therapy. She subsequently experienced severe, treatment-refractory cutaneous viral infections. In adulthood, she developed gynecologic and anal neoplasms associated with chronic viral disease, requiring long-term multidisciplinary management. The second patient presented in early childhood with recurrent respiratory infections, marked lymphoproliferation, and generalized lymphadenopathy. He then developed kidney dysfunction due to light-chain deposition disease. Management included immunoglobulin therapy, and ultimately hematopoietic cell transplantation (HCT), after which he achieved sustained clinical improvement. Genetic testing identified the same homozygous p.R68W substitution in both patients. Despite significantly reduced RAC2 protein expression, patient-derived cells exhibited increased effector signaling in the homozygous state, producing a phenotype that phenocopies dominant gain-of-function RAC2 variants. Functional hyperactivation was not observed in heterozygous cells, supporting a dosage-dependent mechanism. These cases expand the clinical and functional spectrum of RAC2 deficiency and have immediate implications for clinical care. Persistent viral disease with oncogenic complications, bronchiectasis, lymphoproliferation, or progressive organ involvement should prompt consideration of RAC2 testing even beyond infancy. From a diagnostic standpoint, reliance on expression alone may be misleading; incorporating targeted signaling assays is essential for accurate variant interpretation. Therapeutically, HCT can be effective in progressive disease with organ damage, while others may require long-term medical management of chronic viral complications. Recognizing this rare, homozygous p.R68W variant and its functional consequences supports a precision-diagnosis approach to RAC2-related immunodeficiency and refines surveillance and treatment strategies for affected patients.

PMID:41685306 | PMC:PMC12891230 | DOI:10.3389/fimmu.2026.1723142