Chronic granulomatous disease-related inflammatory bowel disease (CGD-IBD) requires effective and safe therapies, as conventional immunosuppressants increase infection risk. Thalidomide, with anti-inflammatory and immunomodulatory effects, may represent a therapeutic option. This study was conducted to explore the preliminary efficacy and safety of thalidomide for CGD-IBD in a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. Patients were randomized to thalidomide or placebo for a 12-wk blinded phase, followed by a 12-wk extension thalidomide phase. The primary endpoint was achievement of remission or a ≥20-point reduction in the Pediatric Ulcerative Colitis Activity Index. Eight male patients were randomized and analyzed. The primary endpoint was achieved by 1/3 of thalidomide patients versus 0/5 in the placebo group during the blinded phase, and by 5/8 in the extension phase. Secondary endpoints and exploratory endoscopy showed improvements. CGD-related infection rates were comparable before and after treatment. Thalidomide met the prespecified efficacy criterion with an acceptable safety profile in CGD-IBD, suggesting a promising therapeutic option that warrants further clinical studies.

Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease with diverse phenotypes. We describe the genetics, phenotypes, and treatment of n = 48 DADA2 patients from Germany, Austria, and Switzerland. We report a high incidence of hematological (83%) and immunological features (85%), a comparatively low anti-tumor necrosis factor full-response rate (58%), and a high decision probability (21%) for hematopoietic cell transplantation (HCT). We establish a correlation between genetic variant ADA2 activity and patient ADA2 activity. Remarkably, lower patient ADA2 activity is predictive of neutropenia and shows a trend toward HCT decision, whereas higher patient ADA2 activity is predictive of vasculitis symptoms. Genetic variants with low residual ADA2 activity are significantly more common among patients receiving HCT. Our study corroborates previous observations connecting ADA2 activity and clinical phenotype, which up to now have been mainly based on in vitro data.

Genomic testing has transformed the diagnosis and management of inborn errors of immunity (IEIs). Despite its rapid uptake, there remains limited guidance for clinicians on which patients should undergo testing. The Australasian Society of Clinical Immunology and Allergy (ASCIA) has developed evidence-based guidelines to support clinicians in identifying individuals who may benefit from genomic testing for suspected IEI. This guideline paper reviews current literature and reports expert consensus to provide practical recommendations on patient selection, testing modalities, and interpretation of results. It outlines clinical scenarios where genomic testing is most likely to yield actionable insights, including early-onset, severe, or atypical immune presentations and familial patterns suggestive of heritable immune dysfunction. The ASCIA guidelines aim to support genomic testing decision-making and ultimately improve diagnostic accuracy, access to timely interventions, and outcomes for individuals with IEI across Australasia and internationally.

CTLA-4 is a critical immune checkpoint that maintains self-tolerance by regulating immune activation. Here, we describe the first case of homozygous CTLA-4 deficiency (CTLA4 S172P/S172P ), presenting with early-onset autoimmunity, lymphoproliferation, and growth failure. Immunological profiling revealed profound T- and B-cell dysregulation, characterized by T-cell hyperproliferation, a TH1-skewed helper T-cell phenotype, and expansion of activated and atypical B-cell subsets. The identified variant led to impaired CTLA-4 protein stability and enhanced lysosomal degradation, resulting in significantly reduced but still detectable total and surface expression and defective CD80 transendocytosis. Abatacept (CTLA-4-Ig) therapy effectively restored immune regulation and controlled disease activity. These findings expand the clinical and mechanistic spectrum of CTLA-4-related disorders, linking residual CTLA-4 function with the severity of immune dysregulation and emphasizing the therapeutic potential of targeted CTLA-4 modulation.

This issue of the Journal of Human Immunity features a study (https://doi.org/10.70962/jhi.20250227) reporting the long-awaited first case of autosomal recessive human CTLA-4 deficiency. Here, the features of this patient are compared and contrasted to those in CTLA-4 haploinsufficient patients, patients treated with CTLA-4 inhibitors, and Ctla4 -/- mice.

In transitional care for patients with primary immunodeficiency diseases (PID) within inborn errors of immunity (IEI), the adult specialty responsible for accepting patients differs depending on the underlying pathology. In general, rheumatology departments, which manage immune dysregulation and infectious diseases, most commonly assume responsibility. However, pulmonology departments often manage patients with recurrent respiratory infections, while hematology departments frequently take care of patients with hematologic abnormalities or those who have undergone hematopoietic stem cell transplantation. In some institutions, infectious disease or general internal medicine departments are responsible for their care, although identifying an appropriate adult department for transition can sometimes be challenging. At Institute of Science Tokyo Hospital, the departments of pediatrics and rheumatology have long collaborated closely in both outpatient and inpatient settings to manage patients with rheumatic diseases and IEI. Since 2020, a transitional care clinic has been established in our department, and we have actively accepted not only patients with rheumatic diseases but also those with IEI. Many patients with PID have an uncomplicated clinical course with appropriate infection control and continued immunoglobulin replacement therapy. However, autoimmune and inflammatory complications are not uncommon, and the use of immunosuppressive therapy increases the risk of opportunistic infections. In both IEI and rheumatic disease patients, treatment is continued with modifications or additions of medications according to the patient’s life stage. Genetic testing plays a key role in the diagnosis of IEI, and in recent years, the number of patients diagnosed in adulthood has increased. In our institution, diagnostic evaluation is conducted in collaboration with the departments of pediatrics and clinical genetics. In this symposium, we will present the current status and challenges of transitional care for patients with IEI, as well as our institutional experience.

Leukocyte adhesion deficiency, type I (LAD-I) is a rare inborn error of immunity characterized by recurrent, severe infections/inflammation and poor wound healing. Little is known about the patient/family experience of severe LAD-I. We conducted a multiple-case study exploring the burdens of illness, caregiving, and treatment in severe LAD-I. Nine caregivers (parents) representing five families with ≥1 child with severe LAD-I participated in individual, in-depth interviews. Memoing and inductive/deductive coding were used to analyze and compare each family's experience. The caregivers described frequent and severe infections, physical and social restrictions, a complex journey to diagnosis, rearranging life around severe LAD-I, financial strain, isolation, and uncertainty. Treatment burden varied by treatment type. This multiple-case study highlights how severe LAD-I affects patients and families. As the first study to address the humanistic burden of LAD-I in patients and caregivers, it is an important contribution to the literature on LAD-I and qualitative methods for investigating the burden of rare disease on families.

Background Inborn errors of immunity (IEI) are rare disorders; characterizing their clinical features and underlying genetic causes is essential for both clinical practice and research. Despite advances, causative genes remain unidentified in many patients. Clarifying the genetic basis of IEI is crucial to deepening our understanding of its pathophysiology and improving patient management. Methods We retrospectively analyzed 100 patients with IEI followed up at National Defense Medical College Hospital between April 2014 and September 2025. Evaluated variables included age, sex, diagnostic category, registration status in the Primary Immunodeficiency Database in Japan version 2 (PIDJ2), use of immunoglobulin replacement therapy (IGRT), and the identification of causative genes. Results Patients ranged in age from 0 to 68 years (median: 19.5 years); 65 were male, and 35 were female. Based on the International Union of Immunological Societies (IUIS) classification, the diagnostic categories were predominantly antibody deficiencies (n = 57), combined immunodeficiencies with associated or syndromic features (n = 12), immunodeficiencies affecting cellular and humoral immunity (n = 10), diseases of immune dysregulation (n = 8), congenital defects of phagocyte number or function (n = 4), autoinflammatory diseases (n = 4), defects in intrinsic and innate immunity (n = 2), phenocopies of inborn errors of immunity (n = 2), and complement deficiencies (n = 1). Forty-seven patients were registered in PIDJ2. IGRT was administered to 43 patients (intravenous: 12; subcutaneous: 31). Causative genes were identified in 51 patients. Among the 41 patients who remained without an identified causative gene (excluding those who had completed follow-up), the most common categories were predominantly antibody deficiencies (n = 25, including 15 with common variable immunodeficiency [CVID]) and immunodeficiencies affecting cellular and humoral immunity (n = 6, including 5 with late-onset combined immunodeficiency). Conclusion This single-center analysis provides a comprehensive overview of the clinical and genetic characteristics of IEI and highlights that many cases, particularly CVID, still lack an identified genetic cause. Expanding PIDJ2 registration and participating in multicenter collaborative studies may facilitate a more comprehensive understanding of IEI pathophysiology.

Background The implementation of newborn screening (NBS) for primary immunodeficiency (PID) has led to an increasing frequency of low T cell receptor excision circle (TREC) results among preterm infants in Neonatal Intensive Care Units (NICUs). However, the diagnostic process poses significant challenges: confirmatory testing requires substantial blood volumes and notifying parents of a potential immune deficiency significantly exacerbates the anxiety of those already dealing with their infant’s fragility. These issues raise critical questions regarding the clinical benefit of early diagnosis in preterm infants and whether these dilemmas are shared across institutions. Methods We conducted a survey among members of the Japanese Neonatologist Association to investigate current management strategies and clinical responses to low TREC levels in preterm infants. Results The survey results highlighted widespread clinical uncertainty. Respondents emphasized the urgent need for preterm-specific cutoff values, optimization of blood sampling timing, the option to defer testing during acute phases, and a deeper understanding of preterm-specific pathophysiology among clinical immunologists. Discussion Neonatal care must account for the physiological immaturity of the immune system. While the NICU provides stringent infection control, the absence of fever does not necessarily indicate immunocompetence. Furthermore, preterm management involves unique constraints, such as limited blood volume and the frequent necessity of blood transfusions, which can complicate the interpretation of TREC results. Clinical dilemmas also extend to essential care: breastfeeding is vital for neurodevelopment and the prevention of complications like necrotizing enterocolitis, and family contact is regarded as a critical medical intervention for psychological support and parent-infant bonding. However, these may be restricted if PID is suspected. Furthermore, the timeline for clinical decision-making is tight, as the first live vaccines are typically administered around 2–3 months of corrected age. Conclusion From the perspective of neonatal medicine, we aim to advocate for a balanced screening framework that ensures the reliable detection of PID while safeguarding the specialized care and well-being of preterm infants.

STAT3 hyper IgE syndrome (STAT3-HIES) is a rare inborn error of immunity characterized by chronic eczema, recurrent bacterial and fungal infections, markedly elevated serum IgE levels, and a broad spectrum of skeletal, dental, vascular, and gastrointestinal manifestations. Despite increasing insight into the genetic and immunologic basis of STAT3-HIES, detailed, treatment-oriented guidance for clinical practice remains limited. This article provides a pragmatic management guideline for STAT3-HIES. Clinical and laboratory criteria that should prompt suspicion and select patients for genetic testing are discussed. The therapeutic sections cover acute and prophylactic antibacterial treatment, antimicrobial eradication strategies, antifungal therapy, and immunoglobulin replacement therapy. The treatment of severe eczema, organ-specific care for lung, skeletal, vascular, and dental involvement, vaccinations, and supportive measures including physiotherapy and psychosocial support, as well as approaches to pregnancy management, family planning, and genetic counseling are outlined. Furthermore, hematopoietic stem cell transplantation is discussed. This management-focused approach complements existing reviews and aims to standardize care for patients with STAT3-HIES across centers and disciplines.