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X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

Eight infants with SCID-X1 had multilineage immune reconstitution after autologous hematopoietic stem-cell transplantation of marrow stem cells transfected with a lentiviral vector containing IL2RG cDNA after busulfan conditioning. Previous infections cleared and functional T cells developed in all eight infants, IgM levels normalized in seven, and three had a response to vaccines.

Correction of the genetic lesion leading to X-linked SCID with first-generation retroviral vectors has been associated with a 25% risk of acute leukemia. A self-inactivating retrovirus appears to retain therapeutic efficacy, with no leukemia yet observed. X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the gene encoding the interleukin-2 receptor γ chain ( IL2RG ) that result in a lack of response to common γ-chain (γc)–dependent cytokines, an absence of T-cell and natural killer (NK)–cell development, and impairment of B-cell function. 1 , 2 Death from community-acquired or opportunistic infection usually occurs before 1 year of age unless allogeneic hematopoietic stem-cell transplantation (HSCT) is performed. The immunologic defect in children with SCID-X1 obviates the requirement for a preparative regimen before transplantation. 3 – 6 Standard allogeneic HSCT with matched-sibling donors is associated with an 85 to 90% overall . . .

The interleukin-2 receptor gamma chain gene ( ) encodes for the common γ chain (γ ) protein, that is a shared signaling component of multiple interleukin receptors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, and plays a pivotal role in lymphocyte development, homeostasis, and function. Mutations in cause X-linked severe combined immunodeficiency (X-SCID) and a broad spectrum of related phenotypes ranging from typical SCID to leaky or atypical presentations, sometimes mimicking common variable immunodeficiency or immune dysregulation syndromes. Over the last decade (2015-2025), advances in molecular diagnostics, next-generation sequencing, and functional immunology have expanded the known mutational spectrum and refined genotype-phenotype correlations. Recent research has uncovered novel hypomorphic variants, revealed the structural basis of receptor dysfunction, and elucidated the impact of specific mutations on JAK-STAT signaling. Longitudinal natural history studies have improved understanding of disease progression in partial loss-of-function cases, while expanded newborn screening for SCID has facilitated earlier diagnosis. Advances in preclinical and clinical gene therapy have addressed historical challenges such as insertional mutagenesis, with emerging protocols achieving stable multilineage immune reconstitution. Moreover, comparative HSCT outcome analyses have informed donor selection, conditioning strategies, and post-transplant care, particularly in resource-limited settings. Improved molecular diagnostics have enabled precision diagnosis in patients with atypical presentations, allowing earlier initiation of curative therapies such as HSCT or gene therapy. Recognition of immune dysregulation, autoimmunity, and malignancy as part of the -related spectrum has refined long-term follow-up protocols. Multidisciplinary care, integrating infectious disease, immunology, and genetics expertise, has become essential for optimizing patient outcomes. Ongoing priorities include the expansion of gene therapy trials to cover hypomorphic and late-presenting cases, refinement of reduced-intensity conditioning regimens to minimize toxicity, and development of targeted molecular therapies to modulate downstream signaling in non-transplant candidates. Global initiatives for SCID newborn screening, coupled with collaborative registries, are expected to improve early diagnosis and equitable access to curative interventions.

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.

Severe combined immunodeficiency (SCID) comprises a group of life-threatening inborn errors of immunity (IEI) characterized by profound T-cell deficiency, frequently accompanied by impaired B cell and natural killer (NK) cell function. X-linked SCID (X-SCID), caused by pathogenic variants in , accounts for approximately 30% of all SCID cases. We describe two male siblings born to consanguineous parents with a family history of early sibling deaths due to severe infections. Patient 1 was a 9-month-old boy who developed persistent cough, chronic diarrhea, and subcutaneous nodules following Bacillus (BCG) vaccination. He was subsequently diagnosed with disseminated BCG infection with concomitant co-infection. Immunological evaluation revealed a T-B+NK- phenotype. Despite intensive antimicrobial treatment, he died of septic shock at 12 months of age. Patient 2, a one-month-old boy, was evaluated early in life because of family history. Immunophenotyping demonstrated absent T cells, normal B cells, and reduced NK cells, along with the absence of a thymic shadow on chest radiography. Next-generation sequencing identified a hemizygous c.667G>T (p.V223F). He received antimicrobial prophylaxis and immunoglobulin replacement therapy; however, he developed disseminated adenovirus infection and died at 8 months of age. Molecular Findings: analyses (UniProt, HOPE, dbNSFP) consistently supported the pathogenic effect of the variant p.V223F. Based on this evidence, we propose that its current classification as \"likely pathogenic\" should be updated to \"pathogenic\". These cases underscore the challenges faced by patients with SCID when timely access to curative therapy is not available. They also highlight the importance of readily accessible but highly informative diagnostic clues, such as the absence of a thymic shadow on chest radiography and the occurrence of severe complications following BCG vaccination. Conclusions: This report expands the known genotypic and phenotypic spectrum of SCID and reinforces the critical need for early diagnosis, appropriate genetic counseling in consanguineous families, and equitable access to newborn screening programs and curative treatments, including hematopoietic stem cell transplantation and gene therapy, in order to improve survival outcomes.

The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free magnesium (Mg²⁺) concentrations. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. We show that decreased intracellular free Mg²⁺ causes defective expression of the natural killer activating receptor NKG2D in natural killer (NK) and CD8⁺ T cells and impairs cytolytic responses against EBV. Notably, magnesium supplementation in MAGT1-deficient patients restores intracellular free Mg²⁺ and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, these findings reveal a specific molecular function of free basal intracellular Mg²⁺ in eukaryotic cells.

Newborn screening (NBS) for severe combined immunodeficiency (SCID) has improved the prognosis of SCID. In Japan, NBS testing (measurement of the T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC)) was launched in 2017 and has expanded nationwide in recent years. In this study, we report a Japanese patient with X-linked SCID with a novel variant identified through NBS. The patient underwent cord blood transplantation (CBT). The patient had no siblings or family history of inborn errors of immunity. He was born at 38 weeks of gestation and weighed 3,072 g. His NBS results revealed TREC 0 copies/10 cells (normal value: >565 copies/10 cells), which was considered suggestive of SCID. The patient was referred to our hospital. Although his lymphocyte count was 1,402/μL, naïve T cells and CD56 natural killer (NK) cells were decreased to 0% and 0.05% of the total lymphocytes, respectively. Flow cytometric measurement testing revealed a decrease in γc protein expression in the B lymphocytes and NK lymphocytes. We identified a hemizygous novel missense variant (c.256A>C, p.Thr86Pro) of . Both and structural analyses revealed that this variant is likely pathogenic. At 3 months of age, he underwent CBT from a human leukocyte antigen-full-matched unrelated donor. The conditioning regimen included fludarabine (180 mg/m ) and targeted busulfan (35 mg×h/L). The patient achieved high-level donor chimerism and immune reconstitution, including B-cell function, at 13 months. Using NBS, the patient was diagnosed as having X-linked SCID with a novel missense variant of . Early diagnosis using NBS tests enables safe hematopoietic stem cell transplantation without complications such as infection. We also found that even SCID with novel variants can be accurately diagnosed using the NBS program. In Japan, the test uptake rate is approximately 80% due to the high number of self-funded screening tests, and it is hoped that the uptake rate will increase in the future.

Cryptococcosis is an opportunistic disease caused by the fungus Cryptococcus neoformans and Cryptococcus gattii . It starts as a pulmonary infection that can spread to other organs, such as the brain, leading to the most serious occurrence of the disease, meningoencephalitis. The humoral response has already been described in limiting the progression of cryptococcosis where the B-1 cell seems to be responsible for producing natural IgM antibodies, crucial for combating fungal infections. The role of the B-1 cell in C. neoformans infection has been initially described, however the role of the humoral response of B-1 cells has not yet been evaluated during C. gattii infections. In the present study we tried to unravel this issue using XID mice, a murine model deficient in the Btk protein which compromises the development of B-1 lymphocytes. We use the XID mice compared to BALB/c mice that are sufficient for the B-1 population during C. gattii infection. Our model of chronic lung infection revealed that XID mice, unlike the sufficient group of B-1, had early mortality with significant weight loss, in addition to reduced levels of IgM and IgG specific to GXM isolated from the capsule of C. neoformans . In addition to this, we observed an increased fungal load in the blood and in the brain. We described an increase in the capsular size of C. gattii and the predominant presence of cytokines with a Th2 profile was also observed in these animals. Thus, the present study strongly points to a higher susceptibility of the XID mouse to C. gattii , which suggests that the presence of B-1 cells and anti-GXM antibodies is fundamental during the control of infection by C. gattii .

X-linked severe immunodeficiency disease (SCID-X1) is an inherited, rare, and life-threating disease. The genetic origin is a defect in the interleukin 2 receptor γ chain ( IL2RG ) gene and patients are classically characterized by absence of T and NK cells, as well as presence of partially-functional B cells. Without any treatment the disease is usually lethal during the first year of life. The treatment of choice for these patients is hematopoietic stem cell transplantation, with an excellent survival rate (>90%) if an HLA-matched sibling donor is available. However, when alternative donors are used, the success and survival rates are often lower. Gene therapy has been developed as an alternative treatment initially using γ-retroviral vectors to correct the defective γ chain in the absence of pre-conditioning treatment. The results were highly promising in SCID-X1 infants, showing long-term T-cell recovery and clinical benefit, although NK and B cell recovery was less robust. However, some infants developed T-cell acute lymphoblastic leukemia after the gene therapy, due to vector-mediated insertional mutagenesis. Consequently, considerable efforts have been made to develop safer vectors. The most recent clinical trials using lentiviral vectors together with a low-dose pre-conditioning regimen have demonstrated excellent sustained T cell recovery, but also B and NK cells, in both children and adults. This review provides an overview about the different gene therapy approaches used over the last 20 years to treat SCID-X1 patients, particularly focusing on lymphoid immune reconstitution, as well as the developments that have improved the process and outcomes.