Research

Br J Haematol. 2025 May 1. doi: 10.1111/bjh.20091. Online ahead of print.

ABSTRACT

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency requiring medical intervention and is heterogeneous in clinical presentation and outcome. Beyond susceptibility to infections, many patients with CVID develop chronic lung disease, enteropathy, granulomatous disease, lymphoproliferation and autoimmunity. Immune thrombocytopenia (ITP) is the most common autoimmune condition associated with CVID, impacting 4%-19% of CVID patients, while CVID is found in 1%-2% of ITP patients. Given that CVID is defined by decreased antibody production, the underlying pathophysiology of CVID-associated ITP remains elusive.

PMID:40312967 | DOI:10.1111/bjh.20091

Front Immunol. 2025 Apr 17;16:1526439. doi: 10.3389/fimmu.2025.1526439. eCollection 2025.

ABSTRACT

BACKGROUND: Opportunistic intramacrophagic infections are well-characterized in adult-onset immunodeficiency associated with neutralizing anti-IFN-γ autoantibodies (nAIGA).

OBJECTIVE: Concomitant autoimmune and neoplastic diseases are rarely described.

METHODS: This study included 50 patients diagnosed with adult-onset immunodeficiency due to nAIGA between 2014-2024. Thirty-three were retrospectively included before January 2022, and 17 out of 295 screened patients were enrolled prospectively since January 2022. Ten patients were excluded due to missing records. All patients had regular follow-ups; anti-IFN-γ titers, autoimmune markers and cancer survey were conducted according to the primary physician’s evaluation.

RESULTS: The median age at diagnosis of adult-onset immunodeficiency was 57 years, and 53% were men. Malignancy occurred in 25%; genitourinary cancer predominated (n=4). Most (93%) patients had at least one positive autoimmune marker. Fifty-eight percent of patients were diagnosed with concomitant autoimmune diseases, and women (65%) predominated. Anti-nuclear antibody was positive in 61%, lupus anticoagulant in 50%, whilst autoimmune thyroiditis markers in 43%. Twenty-two percent of patients required long-term immunomodulation including biologic agents such as rituximab and daratumumab. Three patients (8%) died after a median interval of 9.4 years due to sepsis (n=2) and aggressive urothelial cancer (n=1). Most patients had decreasing nAIGA titers over time; two outliers with persistently high neutralizing antibodies developed late-onset malignancies.

CONCLUSION: Adult-onset immunodeficiency due to nAIGA is a syndrome associated with concomitant autoimmunity. Chronic infection and autoimmune-mediated inflammation may foster neoplastic changes, but the underlying mechanism is still undetermined. Autoimmune disease and cancer surveillance for patients with nAIGA is advised.

PMID:40313931 | PMC:PMC12043703 | DOI:10.3389/fimmu.2025.1526439

N Engl J Med. 2025 May 1;392(17):1698-1709. doi: 10.1056/NEJMoa2407376.

ABSTRACT

BACKGROUND: The β₂ common integrin subunit CD18 is essential for leukocyte-endothelial adhesion and extravasation to inflamed or infected tissue. Damaging variants in ITGB2, which encodes CD18, cause leukocyte adhesion deficiency type I (LAD-I), an inborn error of immunity that leads to frequent life-threatening infections and a high risk of death among affected children. Allogeneic hematopoietic stem-cell transplantation (HSCT) represents a curative treatment but is limited by donor availability, a high incidence of graft-versus-host disease, and graft failure.

METHODS: In a phase 1-2, multinational, open-label study, we enrolled nine children who had severe LAD-I and treated them with marnetegragene-autotemcel (marne-cel), a gene therapy of autologous CD34+ hematopoietic stem cells transduced with a self-inactivating lentiviral vector containing human ITGB2, and followed them for 24 months. The primary efficacy end point of the phase 2 study was survival without allogeneic HSCT (HSCT-free survival) at least 1 year after marne-cel infusion and at 2 years of age among the patients who were younger than 1 year of age at enrollment, tested against a null hypothesis of survival of 39% of the patients. We also report interim data from six patients enrolled in the long-term follow-up study.

RESULTS: Serious adverse events related to myeloablative busulfan conditioning were observed. No adverse events attributed to gene therapy were reported. None of the patients had graft failure. HSCT-free survival was 100% (95% confidence interval [CI], 66 to 100) at 1 year after infusion (P<0.001). All the patients who were enrolled at younger than 1 year of age were alive beyond 2 years of age. Pretreatment neutrophilia and skin abnormalities related to LAD-I resolved. The annualized incidence of infection-related hospitalizations beyond 90 days after engraftment through 24 months after marne-cel infusion was 74.45% lower than the incidence before marne-cel infusion, the annualized incidence of prolonged infection-related hospitalizations was 81.95% lower, and the annualized incidence of prespecified serious infections was 84.90% lower.

CONCLUSIONS: In this study, lentiviral vector-transduced autologous CD34+ HSCT was successful in treating severe LAD-I. (Funded by Rocket Pharmaceuticals and the California Institute for Regenerative Medicine; ClinicalTrials.gov numbers, NCT03812263 and NCT06282432.).

PMID:40305711 | DOI:10.1056/NEJMoa2407376

Yakugaku Zasshi. 2025;145(5):379-386. doi: 10.1248/yakushi.24-00194.

ABSTRACT

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive genetic disorder caused by loss-of-function mutations in the gene encoding adenosine deaminase (ADA) 2. This enzyme catalyzes the deamination reaction of adenosine/2′-deoxyadenosine to inosine/2′-deoxyinosine. DADA2 exhibits a complex clinical presentation, with systemic vasculitis with stroke, bone marrow failure, and immunodeficiency as the major pathologies. Since its discovery in 2014, more than 400 cases have been reported, and the phenotype has expanded significantly. DADA2 generally presents in childhood, although diagnosis in adulthood has also been reported, indicating the need to raise awareness of this disease beyond pediatrics. ADA2 is believed to be relevant in the regulation of the human immune system. Currently, knowledge is accumulating on the association between macrophage polarization into an inflammatory phenotype and systemic vasculitis, upregulation of the type I/II interferon pathway, and neutrophil function. The biochemical characteristics of ADA2 that differ from those of its isozyme ADA1 are a subject of significant research. One of these characteristics, N-glycosylation, plays a vital role in controlling the formation of the functional three-dimensional structure of ADA2. Moreover, with the accumulation of knowledge regarding the dysregulation of innate and adaptive immunity in DADA2 and the biochemical properties of ADA2, effective treatments and diagnostic methods are being established. This review provides an overview of ADA2 properties and DADA2.

PMID:40307021 | DOI:10.1248/yakushi.24-00194

Front Neurol. 2025 Apr 16;16:1555562. doi: 10.3389/fneur.2025.1555562. eCollection 2025.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) is a rare disorder characterized by recurrent swelling episodes, including painful abdominal attacks and life-threatening angioedema of the larynx that significantly affects patients’ quality of life, including sleep. Sleep disorders have not yet been elucidated in HAE patients.

METHODS: This study evaluated sleep quality and insomnia by comparing attack-free periods with abdominal, head-neck, and extremity attacks. Sleep quality and insomnia were assessed using two validated questionnaires with the Basic Scale on Insomnia and Quality of Sleep (BaSIQS) and the Pittsburgh Sleep Quality Index (PSQI): sleep latency, difficulty falling asleep, night awakenings, problems returning to sleep, and overall sleep quality.

RESULTS: The study included 23 HAE patients; the median age was 31 years [interquartile range (IQR): 25-37], with a female predominance (n = 16, 69.5%). During the attack-free period, the median PSQI total score was 5 (IQR: 3.75 7.25), with 56.2% of the participants (n = 13) classified as good sleepers. Total PSQI scores significantly increased during attack periods compared to the attack-free period (median: 10 for abdomen, 8.5 for extremities, and 7.5 for head-neck; p < 0.001 for all). Whereas during the attack-free period, only 40.9% of patients exhibited good sleep quality (BaSIQS <9), with a median score of 10 (IQR: 7-14.2).Scores of BaSIQS significantly increased during angioedema attacks, with medians of 15 (extremity), 16 (abdominal), and 17 (head-neck), reflecting a notable decline in sleep quality. Among the components of PSQI, compared to the attack-free period, scores except the one assessing the need for medication to sleep all domains showed statistically significant increase.

CONCLUSION: This study demonstrates that poor sleep quality, prolonged sleep latency, and increased awakenings are prevalent among HAE patients. Screening for sleep disorders and targeted interventions may help improve disease control and overall quality of life in HAE patients.

PMID:40308220 | PMC:PMC12042759 | DOI:10.3389/fneur.2025.1555562

Front Pediatr. 2025 Apr 16;13:1567164. doi: 10.3389/fped.2025.1567164. eCollection 2025.

ABSTRACT

Patients with nephrotic syndrome are at heightened risk of infections due to the underlying disease pathophysiology and the effects of immunosuppressive therapies. Varicella-zoster virus (VZV) infection can cause severe complications in immunocompromised individuals. Concerns about the safety of live attenuated vaccines in this population persist. Emerging vaccination strategies incorporate pre-vaccination risk stratification algorithms based on immunological criteria. We present a case of a five-year-old male with corticosteroid-dependent nephrotic syndrome, in complete remission on mycophenolate mofetil therapy, who received the varicella vaccine after meeting immunocompetence criteria. Fourteen days post-vaccination, he developed scant vesicular lesions, with VZV DNA detected by PCR via swab. By day 16 post-vaccination, he presented with left-eye panuveitis. VZV DNA was also detected in the blood by PCR. Differentiation of VZV vaccine strains from wild-type strains was not possible. Additionally, molecular testing for VZV in the aqueous humor was not performed. However, given the temporal association with varicella vaccination, the detection of VZV in the blood and cutaneous lesions, and most importantly, the immunosuppression of the patient, post-vaccination ocular varicella was assumed even without an epidemiological history of varicella exposure. This case highlights the importance of a thorough immunocompetence assessment before administering live vaccines to immunosuppressed patients, as well as close post-vaccine monitoring and a high index of suspicion for complications to optimize vaccine safety in this vulnerable group. Patients with nephrotic syndrome require vaccination strategies tailored to their individual risk.

PMID:40309166 | PMC:PMC12041026 | DOI:10.3389/fped.2025.1567164

J Allergy Clin Immunol. 2025 Apr 27:S0091-6749(25)00460-9. doi: 10.1016/j.jaci.2025.04.020. Online ahead of print.

ABSTRACT

The complement system is a central component of innate immunity, orchestrating pathogen clearance while regulating inflammation, tissue repair, and homeostasis. Its activation is tightly controlled by multiple inhibitors to prevent self-damage. However, complement dysregulation is implicated in numerous organ-specific diseases, including paroxysmal nocturnal hemoglobinuria (erythrocytes), atypical hemolytic uremic syndrome (kidneys), and age-related macular degeneration (eyes). Recent discoveries have revealed that complement hyperactivation also drives lymphatic dysfunction, most notably in CHAPLE disease-a rare pediatric disorder caused by biallelic CD55 mutations. Impaired regulation of C3 and C5 convertases leads to unchecked complement and coagulation activation, resulting in membrane attack complex deposition, severe intestinal lymphangiectasia, and protein-losing enteropathy (PLE). Patients typically present with hypoalbuminemia, edema, gastrointestinal symptoms, growth retardation, and recurrent thromboembolic events, reflecting a severe thrombophilic phenotype. C5-blocking antibodies, including pozelimab and eculizumab, transformed CHAPLE management. In a Phase 2/3 study, pozelimab led to normalization of serum albumin levels and notable reductions in hospitalizations and transfusion needs- leading to FDA approval. Emerging evidence suggests that complement-driven PLE may also arise in other pathological contexts, expanding the clinical impact of complement dysregulation. As research progresses, novel diagnostic and therapeutic strategies are expected to emerge for a broader spectrum of complement-mediated lymphatic disorders.

PMID:40300720 | DOI:10.1016/j.jaci.2025.04.020

Allergy Asthma Clin Immunol. 2025 Apr 29;21(1):19. doi: 10.1186/s13223-025-00965-4.

ABSTRACT

BACKGROUND: X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity which occurs secondary to mutations in the XIAP/BIRC4 gene. Disease onset usually manifests within the first few years of life, and is associated with a spectrum of clinical features, secondary to immune dysregulation. Males typically present with refractory chronic colitis, hemophagocytic lymphohistiocytosis, and severe and/or recurrent infections. Laboratory analysis may reveal hypogammaglobulinemia and cytopenias. At present, the only curative treatment is allogenic hematopoietic stem cell transplantation.

CASE PRESENTATION: A 24-year-old gentleman, immigrant from the Democratic Republic of Congo, was referred to outpatient immunology for evaluation of an inborn error of immunity given a past medical history significant for refractory fistulizing Crohn’s disease, arthritis, liver abscesses, prior disseminated tuberculosis, anemia, and recurrent infections. He had been asymptomatic throughout his childhood and adolescence, with no infections or symptoms of inflammatory disease until the age of 19, when he was diagnosed with Crohn’s disease. He was soon after admitted to hospital and was diagnosed with hemophagocytic lymphohistiocytosis. Primary immunodeficiency gene panel testing revealed a nonsense variant XIAP c833C > G p.(Ser278*), which generates a premature stop codon at exon 2 (of total 7 exons). On flow cytometry analysis, XIAP protein expression was significantly reduced, confirming the diagnosis of XIAP deficiency.

CONCLUSION: This is one of the only documented reports of a patient with XIAP deficiency, presenting with symptom-onset in adulthood. This case highlights the need to maintain a high index of suspicion for XIAP deficiency in patients with the appropriate clinical presentation, despite advanced age of presentation.

PMID:40301935 | DOI:10.1186/s13223-025-00965-4

Allergy. 2025 Apr 29. doi: 10.1111/all.16570. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEI) are genetic disorders characterized by recurrent and/or severe infections, autoimmunity, autoinflammation, allergies, and cancer. Despite frequent drug exposures due to recurrent infections and comorbidities, the prevalence and characteristics of drug hypersensitivity reactions (DHR) in pediatric patients with IEI remain understudied.

METHODS: This multicenter, cross-sectional study evaluated 264 pediatric patients with IEI along with a control group (CG) comprising 443 age-matched controls using a stepwise diagnostic approach, including the patient-reported Study Questionnaire (Study-Q), the European Network for Drug Allergy Questionnaire (ENDA-Q), and confirmatory diagnostic testing, including skin testing and drug provocation tests (DPT). The demographic, clinical, and allergic profiles of the IEI patients and CG were compared.

RESULTS: IEI patients (57.6% male) had a median current age of 10 years, with combined immunodeficiencies being the most common phenotype (53.4%). The number of courses for antibiotic use and hospitalization was more frequent in IEI patients compared to CG (p < 0.001). DHR was more common in IEI patients according to Study-Q (p < 0.001) and ENDA-Q (p = 0.002), although proven DHR as a result of confirmatory testing was comparable with CG (1.1% vs. 0.4%, p = 0.368). Despite the fact that suspected DHR in IEI patients was most frequently associated with beta-lactams (47.6%), with 73.9% presenting with urticaria, proven DHR mainly included reactions to radiocontrast agents (n = 2) and ibuprofen (n = 1).

CONCLUSION: Although drug hypersensitivity is often suspected in patients with IEI, proven cases are rare. Standardized protocols, including DPT in drug allergy centers, are essential to differentiate proven allergies from nonallergic reactions, ensure effective treatment, and avoid unnecessary drug restrictions in this unique population.

PMID:40298338 | DOI:10.1111/all.16570

J Med Case Rep. 2025 Apr 28;19(1):193. doi: 10.1186/s13256-025-05237-8.

ABSTRACT

BACKGROUND: X-linked lymphoproliferative syndrome type 2 is a relatively rare primary immunodeficiency disease caused by mutations in XIAP. X-linked lymphoproliferative syndrome type 2 typically occurs in male individuals, while female individuals are carriers of the pathogenic gene mutations. Furthermore, X-linked lymphoproliferative syndrome type 2 has a complex clinical phenotype. We aimed to explore the pathogenesis of X-linked lymphoproliferative syndrome type 2 through genetic testing of a family to provide a basis for clinical diagnosis.

CASE PRESENTATION: The clinical data of a female patient with X-linked lymphoproliferative syndrome type 2 and her family were collected and analyzed. The patient was 2 years 1 months old and of Han Chinese descent. Methylation-sensitive restriction enzyme amplification and capillary electrophoresis were used to detect X chromosome inactivation in the family. A novel mutation, c.910G > T (guanine to thymine), was identified in XIAP in the patient and her brother, but was not detected in the patient’s parents. The proportion of chromosomal inactivation in the female children was 86%, which indicates a moderate inactivation shift and paternal inactivation shift.

CONCLUSION: Close attention should be paid to shifts in X-chromosome inactivation in female children. When a pathogenic gene variant is not detected in a mother with a normal phenotype, gonadal mosaicism cannot be ruled out, and prenatal genetic diagnosis should be performed in the next pregnancy.

PMID:40296086 | DOI:10.1186/s13256-025-05237-8