RARE DISEASE
T-B+ severe combined immunodeficiency due to gamma chain deficiency
T-B+ severe combined immunodeficiency due to gamma chain deficiency
T-B+ severe combined immunodeficiency due to gamma chain deficiency
Synonyms: SCIDX1, T-B+ SCID due to gamma chain deficiency, T-B+ severe combined immunodeficiency, X-linked
Synonyms: SCIDX1, T-B+ SCID due to gamma chain deficiency, T-B+ severe combined immunodeficiency, X-linked
Synonyms: SCIDX1, T-B+ SCID due to gamma chain deficiency, T-B+ severe combined immunodeficiency, X-linked
Drug discovery
2
drugs
With orphan designations
Overview
T-B+ severe combined immunodeficiency due to gamma chain deficiency (SCID-X1) is an X-linked recessive disorder caused by mutations in the IL2RG gene, which encodes the interleukin-2 receptor gamma chain critical for immune cell signaling [1][17]. This results in absent T and natural killer (NK) cells, with B cells present but dysfunctional [1][13]. Infants typically present within the first months of life with severe bacterial, viral, or fungal infections (e.g., Pneumocystis jiroveci), chronic diarrhea, failure to thrive, and graft-versus-host disease from maternal T cells [1][6]. Diagnosis is confirmed via TREC newborn screening, flow cytometry, and genetic testing [1][17].
Therapies
Early hematopoietic stem cell transplantation (HSCT) from HLA-matched donors achieves >90% survival when performed before 3.5 months [6][14].
Gene therapy (experimental) restores immune function in IL2RG-deficient patients without graft-versus-host disease risk [14][6].
Supportive care includes immunoglobulin replacement, antimicrobial prophylaxis, and isolation protocols [1][13].
Categories: rare genetic diseases, rare immunological diseases, rare transplant-related disorders
Research Papers
189 drug discovery papers about T-B+ severe combined immunodeficiency due to gamma chain deficiency, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
189 drug discovery papers about T-B+ severe combined immunodeficiency due to gamma chain deficiency, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2026-07-28 | Prevention of recurrence of severe combined immunodeficiency through preimplantation genetic testing: a case study of a novel IL2RG variant and confirmed maternal somatic mosaicism in Thailand
RESEARCH QUESTION: Can preimplantation genetic testing for monogenic disorders (PGT-M) be effectively implemented to prevent recurrence of X-linked severe combined immunodeficiency (X-SCID) caused by a novel IL2RG variant when conventional parental carrier testing initially yields a negative result? DESIGN: CASE REPORT: A Thai couple with a prior affected child (deceased; T⁻B⁺NK⁻ immunophenotype; IL2RG c.676C > G, p.(Arg226Gly)) underwent whole exome sequencing (WES), which was initially negative in both parents. Subsequent WES reanalysis identified a low-level heterozygous signal (~ 12% allele frequency) in the mother's blood, below the standard 30% calling threshold, consistent with low-level maternal mosaicism. Direct sequencing and PCR-RFLP from buccal swab tissue showed a concordant low-level signal in a second tissue compartment. Six blastocysts obtained via ICSI underwent trophectoderm biopsy for combined PGT-M (targeted to the proband's confirmed variant) and comprehensive chromosomal screening (PGT-A). RESULTS: Four blastocysts were euploid and two aneuploids. Of the euploid embryos, three were mutation-free (wild-type) and one carried the IL2RG c.676C > G variant. A single frozen-thawed embryo transfer of a mutation-free euploid embryo resulted in a confirmed intrauterine pregnancy. Non-invasive prenatal testing (NIPT) at 12 weeks demonstrated low risk for Trisomy 21, 18, and 13, with fetal sex concordant with PGT-A findings. CONCLUSIONS: The novel IL2RG c.676C > G (p.(Arg226Gly)) variant identified at a known mutational hotspot (codon 226) and absent from global variant databases is classified as Likely Pathogenic per ACMG criteria. Low-level maternal mosaicism was subsequently identified in blood and supported by concordant low-level findings in buccal mucosa, clarifying recurrence-risk counselling for this family. PGT-M anchored to the proband's confirmed IL2RG variant successfully identified three transferable, euploid, mutation-free embryos, and transfer of one embryo resulted in an ongoing pregnancy. This case demonstrates that ICSI with PGT-M can prevent X-SCID recurrence even when standard parental carrier testing is initially non-informative, establishing a reproductive workflow applicable to families in whom the proband's variant is confirmed.
2026-07-14 | Base Editing Hematopoietic Stem/Progenitor Cell Gene Therapy for Treatment of X-Linked Severe Combined Immunodeficiency
X-linked Severe Combined Immunodeficiency (XSCID) due to IL2RG loss-of-function mutations typically cause a severe combined cellular and humoral immunodeficiency that is diagnosed and transplanted in infancy. Hypomorphic IL2RG variants with milder phenotypes are generally diagnosed later in life. Early stem cell transplants (allogeneic or autologous gene therapy) performed without conditioning often results in partial immune reconstitution with limited donor engraftment in T cell lineage alone. Defective host B, natural killer (NK), and other cell lineages remain and can cause progressive multi-organ disease. Ex vivo gene therapy using lentivector-transduced autologous hematopoietic stem/progenitor cells (HSPCs) has provided clinical benefit for many previously transplanted older XSCID patients (NCT01306019) and transplant-naïve infants (NCT01512888, NCT03311503). Lentivector transduction functionally corrects XSCID stem cells by semi-random insertion of IL2RG cDNA under the regulation of an engineered promoter. A conversion to gene-corrected immune cells in their respective compartment can take years, particularly in older adult patients. The exact mechanism for this slow progression, whether this is attributable to a relatively weak promoter in the transgenes, is unclear. CRISPR/Cas9 base editing provides the potential for precise gene mutation correction that is devoid of random virus integrations and, critically, restores physiological gene regulation by endogenous promoter. We developed a highly efficient base editing strategy using adenine base editor and respective guide RNAs to repair respective IL2RG mutations (IL2RG p.289X, IL2RG p.Gln235X, IL2RG p.Q144X, and IL2RG p.R226H). Preclinical efficacy and safety data supported a Phase I/II clinical trial to treat XSCID patients with base-edited HSPCs (IND 31037; NCT 06851767). Three patients have been treated to date with base-edited (BE) HSPCs (25 million to 50 million cells per kg/weight). BE HSPC products were well tolerated, with early myeloid recovery within 3 weeks after cell infusion. Gene correction frequencies in the study cell products averaged >80%. Follow-up data at 6 months in the first patient showed robust levels of gene correction in myeloid (70%), B (94%), NK (100%), and, surprisingly, in his T cell compartment (65%) as well, with a corresponding decline in donor T cell chimerism (99% at baseline, 47% at 6 months). Monitoring of the other treated patients is ongoing. We conclude from our preliminary data that gene therapy using BE HSPCs appear very promising for achieving an earlier and more robust multi-lineage immune reconstitution in adult patients using BE HSPCs.
2026-06-01 | Gene Therapy As A Treatment Modality For Severe Combined Immunodeficiency : A Narrative Review
Introduction: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder marked by severe T-cell defects and often B-cell and NK-cell dysfunction, leading to an increased risk of infections. Treated via gene therapy which is the introduction of modified therapeutic genes either ex vivo or in vivo as a DNA segments. Methods: A Narrative review was conducted followed. Literature was searched on MidLine, pubmed central (PMC), Web of science, Elcevier, Scopus using the following keywords: Severe combined immunodeficiency(SCID), gene therapy and genetic disorders between 2015 and 2024. The included papers were case reports and series, cohort studies, case control and randomized controlled trials. Results: The reviewed literature illustrate that gene therapy has reached significant progress in treating (SCID), particularly X-linked SCID (SCID-X1) and ADA-SCID. Viral vectors especially retroviral, lentiviral, and adeno-associated viral (AAV) vectors have been successfully used to recover T-cell immunity and correct genetic defects, with ADA-SCID patients showing stable immune function and reduced adoption on enzyme replacement therapy. The Protection of lentivirus and foamy virus vectors have been improved, reducing dangers like insertional mutagenesis. Despite their biosafety enhancement, non-viral delivery methods are still limited by their lower transfection efficiency. Conclusion: gene therapy has the ability to treat numerous different primary immunodeficiency (PIDs). There are some limits. Important elements to consider are vector and envelope type, transduction technique, cell dose, delivery modality, conditioning regimen, and illness features. Further research is needed.
2026-05-25 | Modeling and correction of SCID-X1 using CRISPR-Cas9 homology-directed repair in human HSPCs.
X-linked severe combined immunodeficiency (SCID-X1) is a severe primary immunodeficiency caused by mutations in the IL2RG gene, a shared subunit of cytokine receptors critical for the development and function of T and natural killer (NK) cells. The standard treatment, allogeneic hematopoietic stem cell transplantation (HSCT), requires a compatible donor and is often associated with significant transplant-related complications. We aimed to develop a more robust and universal gene therapy by ex vivo modification of patient hematopoietic stem and progenitor cells (HSPCs) using the CRISPR-Cas9/rAAV6 gene-editing platform. To evaluate efficiency, we utilized a feeder-free, in vitro platform enabling T and NK cell differentiation from modified HSPCs. We investigated two approaches: the cut-site method (inserting a corrective cassette downstream of the start codon within the IL2RG locus) and a replacement method (replacing the entire IL2RG gene under endogenous regulation). We demonstrated that the cut-site insertion strategy is preferable for SCID-X1 correction, achieving superior homology-directed repair rates, lower toxicity, and significantly improved T and NK cell differentiation, based on phenotypic marker expression. Importantly, corrected patient-derived HSPCs from two SCID-X1 patients, modified using the cut-site approach, successfully demonstrated phenotypic evidence of T cell differentiation. Therefore, our findings firmly establish the feasibility of the cut-site strategy as a universal, high-efficiency, therapeutic solution for SCID-X1.
2026-03-30 | IL2RG-related immunodeficiencies: from SCID to atypical presentations.
The interleukin-2 receptor gamma chain gene (IL2RG) encodes for the common γ chain (γc) 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 IL2RG 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 IL2RG 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 IL2RG-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.
cell therapies
2026-06-30 | Combined immune deficiency caused by a hypomorphic <i>IL2RG</i> variant and disguised as Burkitt leukemia: a clinical case
X-linked severe combined immunodeficiency (X-SCID) is an inborn error of immunity characterized by almost total absence of T and NK cells with normal counts of functionally impaired B cells (T–B+NK–) that is caused by pathogenic variants in the IL2RG gene resulting in early onset of life-threatening infections. Hypomorphic X-SCIDs present with variable clinical features and are characterized by later onset of infectious complications, a wide range of autoimmune manifestations, and increased risk of malignancies. In this article, we report a rare case of atypical X-SCID presenting with partial red cell aplasia and Burkitt leukemia as the first signs of immune dysregulation. Verification of the diagnosis of X-SCID leads to a different treatment approach, including the use of hematopoetic stem cell transplantation as a curative option. It highlights the importance of awareness of inborn errors of immunity among hematologists and oncologists.
2025-04-25 | Roles of Common Gamma Chain on Intestinal Lymphoid Organogenesis using an Animal Model and Patients’ Samples of X-SCID
Background Organ-level research for intestinal lymphoid organogenesis regulated by IL2RG, the gene responsible for X-linked severe combined immunodeficiency (X-SCID), is clinically unavailable in humans. The establishment of in vivo animal model lacking IL2RG could be a powerful tool for gaining deeper insights into the roles of common gamma chain on intestinal immunity in patients with X-SCID. Methods We established an X-SCID animal model, which was first reported by our group, by deleting the IL2RG in pigs, to understand the clinical significance of IL2RG in intestinal lymphoid organogenesis and microenvironment. Pigs with X-SCID underwent bone marrow transplantation (BMT) to mimic the current therapeutic treatment for patients with X-SCID. We investigated the effect of BMT on organ-level immune reconstitution. Moreover, the results were confirmed using serum and fecal samples collected from patients with X-SCID treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) [1]. Results We demonstrated that pigs with X-SCID completely lacked Peyer’s patches (PPs) and IgA production in the small intestine but possessed some dysfunctional intestinal T and B cells. Moreover, pigs with X-SCID developed a heterogeneous intestinal microflora, indicating that X-SCID could be an immune disorder that affects normal intestinal lymphoid organogenesis and microenvironment. Importantly, PP organogenesis in pigs with X-SCID was not completely reconstituted by BMT. Although a few isolated lymphoid follicles developed in the small intestines of BMT-treated pigs with X-SCID, there was no evidence that they contributed to IgA production and normal microflora formation. Consistently, most patients with X-SCID who underwent allo-HSCT showed insufficient IgA production and dysbiosis, especially those with incomplete immune reconstitution and low serum IgG levels after allo-HSCT. Conclusion Our results indicate that common gamma chain has indispensable roles in intestinal lymphoid organogenesis and microenvironment, suggesting that loss of function of IL2RG product is associated with an increased risk of intestinal infections, malnutrition, and dysbiosis in untreated patients with X-SCID. Our animal model indicated that current allo-HSCT for patients with X-SCID may be insufficient to induce complete reconstitution of intestinal lymphoid organogenesis in vivo. Figure 1.
2025-03-31 | Whole Exome Sequencing Identified a Pathogenic IL2RG Variant in Monozygotic Twins with Severe Combined Immunodeficiency
Purpose This study aimed to determine the genetic cause of severe combined immunodeficiency (SCID) in monozygotic twin male infants who presented with recurrent severe infections and disseminated BCG-related complications. Methods Whole Exome Sequencing (WES) was performed on one twin to identify candidate pathogenic variants. The detected IL2RG variant was validated through PCR and Sanger sequencing, and family segregation analysis was conducted. Comprehensive immunological assessments, including T-cell receptor excision circle (TREC) assays and lymphocyte profiling, were employed. High-resolution HLA typing was also carried out to evaluate donor compatibility for hematopoietic stem cell transplantation (HSCT). Results WES revealed a hemizygous c.670C > T (p.Arg224Trp) variant in the IL2RG gene, a change absent from population databases and predicted to be deleterious by in silico tools. Sanger sequencing confirmed the variant in both twins, and maternal heterozygosity was identified, supporting an X-linked recessive inheritance pattern. Clinically, the twins exhibited profound lymphopenia and undetectable TRECs, consistent with a T⁻B⁺NK⁻ immunophenotype. HLA typing demonstrated only partial haplotype matches with the parents, indicating the necessity for a haploidentical transplant approach. Conclusion Integrating genomic analysis with immunological profiling effectively pinpointed a pathogenic IL2RG mutation as the cause of SCID in these twins. Early genetic diagnosis using WES is critical for guiding timely therapeutic interventions such as HSCT or gene therapy and underscores the need for implementing newborn screening and carrier testing programs, particularly in resource-limited settings.
2024-06-06 | Restoring T and B cell generation in X-linked severe combined immunodeficiency mice through hematopoietic stem cells adenine base editing.
Base editing of hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematologic diseases. However, the feasibility of using adenine-base-edited HSPCs for treating X-linked severe combined immunodeficiency (SCID-X1), the influence of dose-response relationships on immune cell generation, and the potential risks have not been demonstrated in vivo. Here, a humanized SCID-X1 mouse model was established, and 86.67% ± 2.52% (n = 3) of mouse hematopoietic stem cell (HSC) pathogenic mutations were corrected, with no single-guide-RNA (sgRNA)-dependent off-target effects detected. Analysis of peripheral blood over 16 weeks post-transplantation in mice with different immunodeficiency backgrounds revealed efficient immune cell generation following transplantation of different amounts of modified HSCs. Therefore, a large-scale infusion of gene-corrected HSCs within a safe range can achieve rapid, stable, and durable immune cell regeneration. Tissue-section staining further demonstrated the restoration of immune organ tissue structures, with no tumor formation in multiple organs. Collectively, these data suggest that base-edited HSCs are a potential therapeutic approach for SCID-X1 and that a threshold infusion dose of gene-corrected cells is required for immune cell regeneration. This study lays a theoretical foundation for the clinical application of base-edited HSCs in treating SCID-X1.
2023-12-18 | Epstein-Barr Virus-negative Diffuse Large B Cell Lymphoma in a X-linked Severe Combined Immunodeficiency Patient: A Very Rare Condition
Severe combined immunodeficiency disorders (SCID) are a genetically heterogeneous group of inherited defects characterized by severe abnormalities of immune system development and function that lead to a wide spectrum in clinical manifestations. A subgroup of patients presents a disabling and life-threatening clinical course. In these cases, allogeneic hematopoietic stem cell transplant provides a curative approach. The occurrence of SCID-associated lymphoproliferative disorders is rare and occur mostly in adenosine deaminase-deficient severe combined immunodeficiency disorders, after allogeneic hematopoietic stem cell transplant. Epstein Barr virus infection is present in the majority of individuals with primary immunodeficiency developing lymphoma, revealing compromised anti-tumour surveillance of virally transformed cells. Herein, we report a rare case of diffuse large B cell lymphoma occurring in an Epstein Barr virus negative, non-transplanted X-linked severe combined immunodeficiency 4-months-old infant, successfully treated with immunotherapy and allogeneic stem cell transplantation. This case suggests that Epstein Barr virus -independent mechanism of neoplastic transformation must take action in severe combined immunodeficiency associated lymphoma and unveils the curative potential of donor T cells after allogeneic transplantation.
proteins
2022-10-03 | Case report: Novel treatment regimen for enterovirus encephalitis in SCID.
Most non-polio enterovirus infections in immunocompetent individuals are acute and self-limiting in nature; however, infection can be severe, chronic and have devastating outcomes in immunocompromised hosts. Therapeutic strategies have predominantly involved supportive care, with the lack of approved antiviral treatments proving challenging for management. We report a case of an 8-month-old child who presented with severe enterovirus encephalitis following gene therapy for X-linked severe combined immunodeficiency (X-SCID) and who demonstrated clinical and microbiological improvement after a novel regimen of favipiravir, fluoxetine, and high-dose intravenous immunoglobulin (IVIg). The patient presented 6 weeks post-gene therapy with rapid neurological deterioration in the context of incomplete immune reconstitution, with microbiological and radiological evidence confirming enterovirus encephalitis. His neurologic examination stabilised 8 weeks after treatment, and he subsequently demonstrated excellent immune recovery. This is the first case report of combined therapy with favipiravir, fluoxetine, and high-dose IVIg in the context of severe enterovirus encephalitis in an immunocompromised host. This case highlights the importance of considering enterovirus encephalitis in immunocompromised patients presenting with both acute and chronic neurological signs, as well as developmental regression. The demonstrated treatment success and the associated low risk of toxicity warrant further investigation of this therapeutic regimen.
2021-12-13 | Case Report: Interleukin-2 Receptor Common Gamma Chain Defect Presented as a Hyper-IgE Syndrome.
X-linked severe combined immunodeficiency (X-SCID) is caused by mutations of IL2RG, the gene encoding the interleukin common gamma chain (IL-2Rγ or γc) of cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Hypomorphic mutations of IL2RG may cause combined immunodeficiencies with atypical clinical and immunological presentations. Here, we report a clinical, immunological, and functional characterization of a missense mutation in exon 1 (c.115G>A; p. Asp39Asn) of IL2RG in a 7-year-old boy. The patient suffered from recurrent sinopulmonary infections and refractory eczema. His total lymphocyte counts have remained normal despite skewed T cell subsets, with a pronounced serum IgE elevation. Surface expression of IL-2Rγ was reduced on his lymphocytes. Signal transducer and activator of transcription (STAT) phosphorylation in response to IL-2, IL-4, and IL-7 showed a partially preserved receptor function. T-cell proliferation in response to mitogens and anti-CD3/anti-CD28 monoclonal antibodies was significantly reduced. Further analysis revealed a decreased percentage of CD4+ T cells capable of secreting IFN-γ, but not IL-4 or IL-17. Studies on the functional consequences of IL-2Rγ variants are important to get more insight into the pathogenesis of atypical phenotypes which may lay the ground for novel therapeutic strategies.
2020-09-17 | Review: Oncogenic Insertional Mutagenesis as a Consequence of Retroviral Gene Therapy for X-Linked Severe Combined Immunodeficiency Disease.
For X-linked severe combined immunodeficiency (SCID-X1), the practice of gene therapy has revealed an unusual effect: insertional mutagenesis that can lead to leukemia. Even though incorporation of the retrovirus close to the oncogene for T-cell acute lymphoblastic leukemia (T-ALL), LIM-only protein 2 (LMO2) is observed frequently, but it is not clear why LMO2 expression is affected. It was demonstrated that in all the typical T-ALL oncogenes, there is mainly transcription of LMO2 in CD34+ progenitor cells. LYL1, TAN1, and TAL1 are very important intensification factors that are classically used in the gene therapy for copying LMO2 when they are stimulated. For this reason, oncogenes are susceptible to amalgamation with viruses. The IL-2R-gamma (IL-2 receptor γ chain) was found to be a supporting oncogene to LMO2. Nevertheless it was illustrated that excessive expression of IL-2R-gamma did not affect T-cell growth. In comparison to it, the excessive expression of LMO2 in CD34+ cells can cause ongoing increases in the development of T cells. Conversely, there is no effect on the development of B cells and myeloid cells. This information helps explain why LMO2 is mostly affected by various identified T-ALL oncogenes. In addition, throughout the process of T-cell development, expression of IL2R-gamma mediated by retrovirus may not always be oncogenic. As an alternative, replacement of signals of common IL-7 receptors may increase development of T cells wherever LMO2 was expressed and caused abnormal thymocyte development.
2015-06-16 | Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice.
Hematopoietic stem cell (HSC) gene therapy is a demonstrated effective treatment for X-linked severe combined immunodeficiency (SCID-X1), but B-cell reconstitution and function has been deficient in many of the gene therapy treated patients. Cytoreductive preconditioning is known to improve HSC engraftment, but in general it is not considered for SCID-X1 since the poor health of most of these patients at diagnosis and the risk of toxicity preclude the conditioning used in standard bone marrow stem cell transplantation. We hypothesized that mobilization of HSC by granulocyte colony-stimulating factor (G-CSF) should create temporary space in bone marrow niches to improve engraftment and thereby B-cell reconstitution. In the present pilot study supplementing our earlier preclinical evaluation (Huston et al., 2011), Il2rg(-/-) mice pretreated with G-CSF were transplanted with wild-type lineage negative (Lin(-)) cells or Il2rg(-/-) Lin(-) cells transduced with therapeutic IL2RG lentiviral vectors. Mice were monitored for reconstitution of lymphocyte populations, level of donor cell chimerism, and antibody responses as compared to 2 Gy total body irradiation (TBI), previously found effective in promoting B-cell reconstitution. The results demonstrate that G-CSF promotes B-cell reconstitution similar to low-dose TBI and provides proof of principle for an alternative approach to improve efficacy of gene therapy in SCID patients without adverse effects associated with cytoreductive conditioning.
2012-03-20 | IL-21 is the primary common γ chain-binding cytokine required for human B-cell differentiation in vivo.
SCID resulting from mutations in IL2RG or JAK3 is characterized by lack of T and natural killer cells; B cells are present in normal number, but antibody responses are defective. Hematopoietic cell transplantation (HCT) is curative for SCID. However, B-cell dysfunction persists in a substantial proportion of patients. We hypothesized that impaired B-cell responses after HCT in IL2RG/JAK3 deficiency results from poor donor B-cell engraftment and defective γc-dependent cytokine signaling in host B cells. To test this, and to identify which γc cytokine(s) is critical for humoral immunity, we studied 28 transplanted patients with IL2RG/JAK3 deficiency. Lack of donor B-cell engraftment associated with persistent humoral dysfunction and significantly reduced memory B cells. B-cell proliferation induced by CD40L alone or together with CpG, anti-Ig, IL-4, IL-10, or IL-13 was comparable in healthy controls and in post-HCT SCID patients, irrespective of their chimerism status. However, in vitro stimulation with CD40L/IL-21 induced B-cell proliferation, plasmablast differentiation, and antibody secretion in patients with donor B cells, but not in patients with autologous B cells. These data imply that IL-21-mediated signaling is critical for long-lived humoral immunity and to restore antibody responses in IL2RG/JAK3-deficient patients after HCT. Furthermore, in vitro stimulation with CD40L/IL-21 can predict in vivo B-cell immunity in IL2RG/JAK3 SCID after transplantation.
small molecules
2024-09-05 | Unrelated cord blood transplantation using minimal-intensity conditioning in a 1.5-month-old infant with X-linked severe combined immunodeficiency.
Severe combined immunodeficiency (SCID) is a heterogenous disorder with profound deficiency of T/B-cell functions. The best SCID therapy requires hematopoietic stem cell transplantation (HSCT) early in life. HSCT with conditioning is necessary to achieve a long-term reconstitution of B-cell functions. However, conditioning may aggravate pre-existing infection and cause transplant-related toxicity, especially in very young infants. Hence, the intensity of conditioning should be reduced to allow the reconstitution of immunity including B cells to the extent that prevents transplant-related toxicity and delayed complications. An infant with a family history of X-linked SCID (X-SCID) was diagnosed with X-SCID disorder soon after birth. The infant exhibited cytomegalovirus (CMV) infection despite being strictly isolated. At 1.5 months of age, we performed an unrelated cord blood transplantation (CBT) with a less intensity conditioning regimen: fludarabine (125 mg/m2) + melphalan (80 mg/m2). We evaluated the efficacy of reconstitution by assessing B-cell function and growth and psychomotor development at 5 years and 7 months after CBT. The clinical course after CBT was uneventful after CBT. The CMV infection was fully controlled by ganciclovir or foscavir therapy, which was discontinued at day 55 after CBT. Furthermore, immunoglobulin (Ig) replacement therapy was also discontinued at 6 months after CBT. A sufficient proportion of CD27+ memory B cells was developed, which was essential for an effective vaccination and prevention of infections. While the B-cell chimerism became recipient-dominant, the Ig replacement therapy was substituted by very successful post-vaccine immunity acquisition after CBT. The analysis of the general developmental parameters showed that chemotherapy did not cause any delay in growth and psychomotor development. The CBT therapy with this conditioning regimen was well tolerated and induced an effective reconstitution of B-cell functions in an X-SCID infant under the 3 months of age.
2022-02-03 | Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.
The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.
2021-06-22 | X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure.
We previously reported the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib improve outcomes in a mouse model of polymicrobial sepsis. Now we show that genetic deficiency of the BTK gene alone in Xid mice confers protection against cardiac, renal, and liver injury in polymicrobial sepsis and reduces hyperimmune stimulation ("cytokine storm") induced by an overwhelming bacterial infection. Protection is due in part to enhanced bacterial phagocytosis in vivo, changes in lipid metabolism and decreased activation of NF-κB and the NLRP3 inflammasome. The inactivation of BTK leads to reduced innate immune cell recruitment and a phenotypic switch from M1 to M2 macrophages, aiding in the resolution of sepsis. We have also found that BTK expression in humans is increased in the blood of septic non-survivors, while lower expression is associated with survival from sepsis. Importantly no further reduction in organ damage, cytokine production, or changes in plasma metabolites is seen in Xid mice treated with the BTK inhibitor ibrutinib, demonstrating that the protective effects of BTK inhibitors in polymicrobial sepsis are mediated solely by inhibition of BTK and not by off-target effects of this class of drugs.
2019-11-13 | The Common Cytokine Receptor γ Chain Family of Cytokines.
Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on their sharing the common cytokine receptor γ chain (γc), which was originally discovered as the third receptor component of the IL-2 receptor, IL-2Rγ. The IL2RG gene is located on the X chromosome and is mutated in humans with X-linked severe combined immunodeficiency (XSCID). The breadth of the defects in XSCID could not be explained solely by defects in IL-2 signaling, and it is now clear that γc is a shared receptor component of the six cytokines noted above, making XSCID a disease of defective cytokine signaling. Janus kinase (JAK)3 associates with γc, and JAK3-deficient SCID phenocopies XSCID, findings that served to stimulate the development of JAK3 inhibitors as immunosuppressants. γc family cytokines collectively control broad aspects of lymphocyte development, growth, differentiation, and survival, and these cytokines are clinically important, related to allergic and autoimmune diseases and cancer as well as immunodeficiency. In this review, we discuss the actions of these cytokines, their critical biological roles and signaling pathways, focusing mainly on JAK/STAT (signal transducers and activators of transcription) signaling, and how this information is now being used in clinical therapeutic efforts.
2019-09-16 | The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications.
The common cytokine receptor γ chain, γc, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γc results in X-linked severe combined immunodeficiency in humans, and γc family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.
other
2021-11-02 | Case Report: Reactive Lymphohistiocytic Proliferation in Infant With a Novel Nonsense Variant of IL2RG Who Received BCG Vaccine
We present here a male young infant with X-linked severe combined immunodeficiency (MIM#300400) due to the novel nonsense variant of IL2RG (interleukin 2 receptor, gamma; MIM#308380), NM_000206.2( IL2RG ):c.820_823dup p.Ser275Asnfs * 29. He developed aggressive reactive lymphohistiocytic proliferation after receiving the live-attenuated Bacillus Calmette-Guérin (BCG) vaccine at birth. This report advocates for modifying the current practice of early use of BCG. The natural history of his disease also suggests considering IL2RG variants as a potential cause of “X-linked recessive Mendelian susceptibility to mycobacterial disease” (MSMD). His reactive lymphohistiocytic proliferation and massive hepatosplenomegaly simulated hemophagocytic lymphohistiocytosis (HLH, likely triggered by the BCG disease). This entity was masked by the absence of fever and markedly elevated inflammatory biomarkers. Thus, his findings stimulate discussion on the need to modify the diagnostic criteria of HLH, in order to accommodate conditions, such IL2RG variants that block systemic inflammation.
gene therapies
2026-07-28 | Prevention of recurrence of severe combined immunodeficiency through preimplantation genetic testing: a case study of a novel IL2RG variant and confirmed maternal somatic mosaicism in Thailand
RESEARCH QUESTION: Can preimplantation genetic testing for monogenic disorders (PGT-M) be effectively implemented to prevent recurrence of X-linked severe combined immunodeficiency (X-SCID) caused by a novel IL2RG variant when conventional parental carrier testing initially yields a negative result? DESIGN: CASE REPORT: A Thai couple with a prior affected child (deceased; T⁻B⁺NK⁻ immunophenotype; IL2RG c.676C > G, p.(Arg226Gly)) underwent whole exome sequencing (WES), which was initially negative in both parents. Subsequent WES reanalysis identified a low-level heterozygous signal (~ 12% allele frequency) in the mother's blood, below the standard 30% calling threshold, consistent with low-level maternal mosaicism. Direct sequencing and PCR-RFLP from buccal swab tissue showed a concordant low-level signal in a second tissue compartment. Six blastocysts obtained via ICSI underwent trophectoderm biopsy for combined PGT-M (targeted to the proband's confirmed variant) and comprehensive chromosomal screening (PGT-A). RESULTS: Four blastocysts were euploid and two aneuploids. Of the euploid embryos, three were mutation-free (wild-type) and one carried the IL2RG c.676C > G variant. A single frozen-thawed embryo transfer of a mutation-free euploid embryo resulted in a confirmed intrauterine pregnancy. Non-invasive prenatal testing (NIPT) at 12 weeks demonstrated low risk for Trisomy 21, 18, and 13, with fetal sex concordant with PGT-A findings. CONCLUSIONS: The novel IL2RG c.676C > G (p.(Arg226Gly)) variant identified at a known mutational hotspot (codon 226) and absent from global variant databases is classified as Likely Pathogenic per ACMG criteria. Low-level maternal mosaicism was subsequently identified in blood and supported by concordant low-level findings in buccal mucosa, clarifying recurrence-risk counselling for this family. PGT-M anchored to the proband's confirmed IL2RG variant successfully identified three transferable, euploid, mutation-free embryos, and transfer of one embryo resulted in an ongoing pregnancy. This case demonstrates that ICSI with PGT-M can prevent X-SCID recurrence even when standard parental carrier testing is initially non-informative, establishing a reproductive workflow applicable to families in whom the proband's variant is confirmed.
2026-07-14 | Base Editing Hematopoietic Stem/Progenitor Cell Gene Therapy for Treatment of X-Linked Severe Combined Immunodeficiency
X-linked Severe Combined Immunodeficiency (XSCID) due to IL2RG loss-of-function mutations typically cause a severe combined cellular and humoral immunodeficiency that is diagnosed and transplanted in infancy. Hypomorphic IL2RG variants with milder phenotypes are generally diagnosed later in life. Early stem cell transplants (allogeneic or autologous gene therapy) performed without conditioning often results in partial immune reconstitution with limited donor engraftment in T cell lineage alone. Defective host B, natural killer (NK), and other cell lineages remain and can cause progressive multi-organ disease. Ex vivo gene therapy using lentivector-transduced autologous hematopoietic stem/progenitor cells (HSPCs) has provided clinical benefit for many previously transplanted older XSCID patients (NCT01306019) and transplant-naïve infants (NCT01512888, NCT03311503). Lentivector transduction functionally corrects XSCID stem cells by semi-random insertion of IL2RG cDNA under the regulation of an engineered promoter. A conversion to gene-corrected immune cells in their respective compartment can take years, particularly in older adult patients. The exact mechanism for this slow progression, whether this is attributable to a relatively weak promoter in the transgenes, is unclear. CRISPR/Cas9 base editing provides the potential for precise gene mutation correction that is devoid of random virus integrations and, critically, restores physiological gene regulation by endogenous promoter. We developed a highly efficient base editing strategy using adenine base editor and respective guide RNAs to repair respective IL2RG mutations (IL2RG p.289X, IL2RG p.Gln235X, IL2RG p.Q144X, and IL2RG p.R226H). Preclinical efficacy and safety data supported a Phase I/II clinical trial to treat XSCID patients with base-edited HSPCs (IND 31037; NCT 06851767). Three patients have been treated to date with base-edited (BE) HSPCs (25 million to 50 million cells per kg/weight). BE HSPC products were well tolerated, with early myeloid recovery within 3 weeks after cell infusion. Gene correction frequencies in the study cell products averaged >80%. Follow-up data at 6 months in the first patient showed robust levels of gene correction in myeloid (70%), B (94%), NK (100%), and, surprisingly, in his T cell compartment (65%) as well, with a corresponding decline in donor T cell chimerism (99% at baseline, 47% at 6 months). Monitoring of the other treated patients is ongoing. We conclude from our preliminary data that gene therapy using BE HSPCs appear very promising for achieving an earlier and more robust multi-lineage immune reconstitution in adult patients using BE HSPCs.
2026-06-01 | Gene Therapy As A Treatment Modality For Severe Combined Immunodeficiency : A Narrative Review
Introduction: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder marked by severe T-cell defects and often B-cell and NK-cell dysfunction, leading to an increased risk of infections. Treated via gene therapy which is the introduction of modified therapeutic genes either ex vivo or in vivo as a DNA segments. Methods: A Narrative review was conducted followed. Literature was searched on MidLine, pubmed central (PMC), Web of science, Elcevier, Scopus using the following keywords: Severe combined immunodeficiency(SCID), gene therapy and genetic disorders between 2015 and 2024. The included papers were case reports and series, cohort studies, case control and randomized controlled trials. Results: The reviewed literature illustrate that gene therapy has reached significant progress in treating (SCID), particularly X-linked SCID (SCID-X1) and ADA-SCID. Viral vectors especially retroviral, lentiviral, and adeno-associated viral (AAV) vectors have been successfully used to recover T-cell immunity and correct genetic defects, with ADA-SCID patients showing stable immune function and reduced adoption on enzyme replacement therapy. The Protection of lentivirus and foamy virus vectors have been improved, reducing dangers like insertional mutagenesis. Despite their biosafety enhancement, non-viral delivery methods are still limited by their lower transfection efficiency. Conclusion: gene therapy has the ability to treat numerous different primary immunodeficiency (PIDs). There are some limits. Important elements to consider are vector and envelope type, transduction technique, cell dose, delivery modality, conditioning regimen, and illness features. Further research is needed.
2026-05-25 | Modeling and correction of SCID-X1 using CRISPR-Cas9 homology-directed repair in human HSPCs.
X-linked severe combined immunodeficiency (SCID-X1) is a severe primary immunodeficiency caused by mutations in the IL2RG gene, a shared subunit of cytokine receptors critical for the development and function of T and natural killer (NK) cells. The standard treatment, allogeneic hematopoietic stem cell transplantation (HSCT), requires a compatible donor and is often associated with significant transplant-related complications. We aimed to develop a more robust and universal gene therapy by ex vivo modification of patient hematopoietic stem and progenitor cells (HSPCs) using the CRISPR-Cas9/rAAV6 gene-editing platform. To evaluate efficiency, we utilized a feeder-free, in vitro platform enabling T and NK cell differentiation from modified HSPCs. We investigated two approaches: the cut-site method (inserting a corrective cassette downstream of the start codon within the IL2RG locus) and a replacement method (replacing the entire IL2RG gene under endogenous regulation). We demonstrated that the cut-site insertion strategy is preferable for SCID-X1 correction, achieving superior homology-directed repair rates, lower toxicity, and significantly improved T and NK cell differentiation, based on phenotypic marker expression. Importantly, corrected patient-derived HSPCs from two SCID-X1 patients, modified using the cut-site approach, successfully demonstrated phenotypic evidence of T cell differentiation. Therefore, our findings firmly establish the feasibility of the cut-site strategy as a universal, high-efficiency, therapeutic solution for SCID-X1.
2026-03-30 | IL2RG-related immunodeficiencies: from SCID to atypical presentations.
The interleukin-2 receptor gamma chain gene (IL2RG) encodes for the common γ chain (γc) 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 IL2RG 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 IL2RG 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 IL2RG-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.
cell therapies
2026-06-30 | Combined immune deficiency caused by a hypomorphic <i>IL2RG</i> variant and disguised as Burkitt leukemia: a clinical case
X-linked severe combined immunodeficiency (X-SCID) is an inborn error of immunity characterized by almost total absence of T and NK cells with normal counts of functionally impaired B cells (T–B+NK–) that is caused by pathogenic variants in the IL2RG gene resulting in early onset of life-threatening infections. Hypomorphic X-SCIDs present with variable clinical features and are characterized by later onset of infectious complications, a wide range of autoimmune manifestations, and increased risk of malignancies. In this article, we report a rare case of atypical X-SCID presenting with partial red cell aplasia and Burkitt leukemia as the first signs of immune dysregulation. Verification of the diagnosis of X-SCID leads to a different treatment approach, including the use of hematopoetic stem cell transplantation as a curative option. It highlights the importance of awareness of inborn errors of immunity among hematologists and oncologists.
2025-04-25 | Roles of Common Gamma Chain on Intestinal Lymphoid Organogenesis using an Animal Model and Patients’ Samples of X-SCID
Background Organ-level research for intestinal lymphoid organogenesis regulated by IL2RG, the gene responsible for X-linked severe combined immunodeficiency (X-SCID), is clinically unavailable in humans. The establishment of in vivo animal model lacking IL2RG could be a powerful tool for gaining deeper insights into the roles of common gamma chain on intestinal immunity in patients with X-SCID. Methods We established an X-SCID animal model, which was first reported by our group, by deleting the IL2RG in pigs, to understand the clinical significance of IL2RG in intestinal lymphoid organogenesis and microenvironment. Pigs with X-SCID underwent bone marrow transplantation (BMT) to mimic the current therapeutic treatment for patients with X-SCID. We investigated the effect of BMT on organ-level immune reconstitution. Moreover, the results were confirmed using serum and fecal samples collected from patients with X-SCID treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) [1]. Results We demonstrated that pigs with X-SCID completely lacked Peyer’s patches (PPs) and IgA production in the small intestine but possessed some dysfunctional intestinal T and B cells. Moreover, pigs with X-SCID developed a heterogeneous intestinal microflora, indicating that X-SCID could be an immune disorder that affects normal intestinal lymphoid organogenesis and microenvironment. Importantly, PP organogenesis in pigs with X-SCID was not completely reconstituted by BMT. Although a few isolated lymphoid follicles developed in the small intestines of BMT-treated pigs with X-SCID, there was no evidence that they contributed to IgA production and normal microflora formation. Consistently, most patients with X-SCID who underwent allo-HSCT showed insufficient IgA production and dysbiosis, especially those with incomplete immune reconstitution and low serum IgG levels after allo-HSCT. Conclusion Our results indicate that common gamma chain has indispensable roles in intestinal lymphoid organogenesis and microenvironment, suggesting that loss of function of IL2RG product is associated with an increased risk of intestinal infections, malnutrition, and dysbiosis in untreated patients with X-SCID. Our animal model indicated that current allo-HSCT for patients with X-SCID may be insufficient to induce complete reconstitution of intestinal lymphoid organogenesis in vivo. Figure 1.
2025-03-31 | Whole Exome Sequencing Identified a Pathogenic IL2RG Variant in Monozygotic Twins with Severe Combined Immunodeficiency
Purpose This study aimed to determine the genetic cause of severe combined immunodeficiency (SCID) in monozygotic twin male infants who presented with recurrent severe infections and disseminated BCG-related complications. Methods Whole Exome Sequencing (WES) was performed on one twin to identify candidate pathogenic variants. The detected IL2RG variant was validated through PCR and Sanger sequencing, and family segregation analysis was conducted. Comprehensive immunological assessments, including T-cell receptor excision circle (TREC) assays and lymphocyte profiling, were employed. High-resolution HLA typing was also carried out to evaluate donor compatibility for hematopoietic stem cell transplantation (HSCT). Results WES revealed a hemizygous c.670C > T (p.Arg224Trp) variant in the IL2RG gene, a change absent from population databases and predicted to be deleterious by in silico tools. Sanger sequencing confirmed the variant in both twins, and maternal heterozygosity was identified, supporting an X-linked recessive inheritance pattern. Clinically, the twins exhibited profound lymphopenia and undetectable TRECs, consistent with a T⁻B⁺NK⁻ immunophenotype. HLA typing demonstrated only partial haplotype matches with the parents, indicating the necessity for a haploidentical transplant approach. Conclusion Integrating genomic analysis with immunological profiling effectively pinpointed a pathogenic IL2RG mutation as the cause of SCID in these twins. Early genetic diagnosis using WES is critical for guiding timely therapeutic interventions such as HSCT or gene therapy and underscores the need for implementing newborn screening and carrier testing programs, particularly in resource-limited settings.
2024-06-06 | Restoring T and B cell generation in X-linked severe combined immunodeficiency mice through hematopoietic stem cells adenine base editing.
Base editing of hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematologic diseases. However, the feasibility of using adenine-base-edited HSPCs for treating X-linked severe combined immunodeficiency (SCID-X1), the influence of dose-response relationships on immune cell generation, and the potential risks have not been demonstrated in vivo. Here, a humanized SCID-X1 mouse model was established, and 86.67% ± 2.52% (n = 3) of mouse hematopoietic stem cell (HSC) pathogenic mutations were corrected, with no single-guide-RNA (sgRNA)-dependent off-target effects detected. Analysis of peripheral blood over 16 weeks post-transplantation in mice with different immunodeficiency backgrounds revealed efficient immune cell generation following transplantation of different amounts of modified HSCs. Therefore, a large-scale infusion of gene-corrected HSCs within a safe range can achieve rapid, stable, and durable immune cell regeneration. Tissue-section staining further demonstrated the restoration of immune organ tissue structures, with no tumor formation in multiple organs. Collectively, these data suggest that base-edited HSCs are a potential therapeutic approach for SCID-X1 and that a threshold infusion dose of gene-corrected cells is required for immune cell regeneration. This study lays a theoretical foundation for the clinical application of base-edited HSCs in treating SCID-X1.
2023-12-18 | Epstein-Barr Virus-negative Diffuse Large B Cell Lymphoma in a X-linked Severe Combined Immunodeficiency Patient: A Very Rare Condition
Severe combined immunodeficiency disorders (SCID) are a genetically heterogeneous group of inherited defects characterized by severe abnormalities of immune system development and function that lead to a wide spectrum in clinical manifestations. A subgroup of patients presents a disabling and life-threatening clinical course. In these cases, allogeneic hematopoietic stem cell transplant provides a curative approach. The occurrence of SCID-associated lymphoproliferative disorders is rare and occur mostly in adenosine deaminase-deficient severe combined immunodeficiency disorders, after allogeneic hematopoietic stem cell transplant. Epstein Barr virus infection is present in the majority of individuals with primary immunodeficiency developing lymphoma, revealing compromised anti-tumour surveillance of virally transformed cells. Herein, we report a rare case of diffuse large B cell lymphoma occurring in an Epstein Barr virus negative, non-transplanted X-linked severe combined immunodeficiency 4-months-old infant, successfully treated with immunotherapy and allogeneic stem cell transplantation. This case suggests that Epstein Barr virus -independent mechanism of neoplastic transformation must take action in severe combined immunodeficiency associated lymphoma and unveils the curative potential of donor T cells after allogeneic transplantation.
proteins
2022-10-03 | Case report: Novel treatment regimen for enterovirus encephalitis in SCID.
Most non-polio enterovirus infections in immunocompetent individuals are acute and self-limiting in nature; however, infection can be severe, chronic and have devastating outcomes in immunocompromised hosts. Therapeutic strategies have predominantly involved supportive care, with the lack of approved antiviral treatments proving challenging for management. We report a case of an 8-month-old child who presented with severe enterovirus encephalitis following gene therapy for X-linked severe combined immunodeficiency (X-SCID) and who demonstrated clinical and microbiological improvement after a novel regimen of favipiravir, fluoxetine, and high-dose intravenous immunoglobulin (IVIg). The patient presented 6 weeks post-gene therapy with rapid neurological deterioration in the context of incomplete immune reconstitution, with microbiological and radiological evidence confirming enterovirus encephalitis. His neurologic examination stabilised 8 weeks after treatment, and he subsequently demonstrated excellent immune recovery. This is the first case report of combined therapy with favipiravir, fluoxetine, and high-dose IVIg in the context of severe enterovirus encephalitis in an immunocompromised host. This case highlights the importance of considering enterovirus encephalitis in immunocompromised patients presenting with both acute and chronic neurological signs, as well as developmental regression. The demonstrated treatment success and the associated low risk of toxicity warrant further investigation of this therapeutic regimen.
2021-12-13 | Case Report: Interleukin-2 Receptor Common Gamma Chain Defect Presented as a Hyper-IgE Syndrome.
X-linked severe combined immunodeficiency (X-SCID) is caused by mutations of IL2RG, the gene encoding the interleukin common gamma chain (IL-2Rγ or γc) of cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Hypomorphic mutations of IL2RG may cause combined immunodeficiencies with atypical clinical and immunological presentations. Here, we report a clinical, immunological, and functional characterization of a missense mutation in exon 1 (c.115G>A; p. Asp39Asn) of IL2RG in a 7-year-old boy. The patient suffered from recurrent sinopulmonary infections and refractory eczema. His total lymphocyte counts have remained normal despite skewed T cell subsets, with a pronounced serum IgE elevation. Surface expression of IL-2Rγ was reduced on his lymphocytes. Signal transducer and activator of transcription (STAT) phosphorylation in response to IL-2, IL-4, and IL-7 showed a partially preserved receptor function. T-cell proliferation in response to mitogens and anti-CD3/anti-CD28 monoclonal antibodies was significantly reduced. Further analysis revealed a decreased percentage of CD4+ T cells capable of secreting IFN-γ, but not IL-4 or IL-17. Studies on the functional consequences of IL-2Rγ variants are important to get more insight into the pathogenesis of atypical phenotypes which may lay the ground for novel therapeutic strategies.
2020-09-17 | Review: Oncogenic Insertional Mutagenesis as a Consequence of Retroviral Gene Therapy for X-Linked Severe Combined Immunodeficiency Disease.
For X-linked severe combined immunodeficiency (SCID-X1), the practice of gene therapy has revealed an unusual effect: insertional mutagenesis that can lead to leukemia. Even though incorporation of the retrovirus close to the oncogene for T-cell acute lymphoblastic leukemia (T-ALL), LIM-only protein 2 (LMO2) is observed frequently, but it is not clear why LMO2 expression is affected. It was demonstrated that in all the typical T-ALL oncogenes, there is mainly transcription of LMO2 in CD34+ progenitor cells. LYL1, TAN1, and TAL1 are very important intensification factors that are classically used in the gene therapy for copying LMO2 when they are stimulated. For this reason, oncogenes are susceptible to amalgamation with viruses. The IL-2R-gamma (IL-2 receptor γ chain) was found to be a supporting oncogene to LMO2. Nevertheless it was illustrated that excessive expression of IL-2R-gamma did not affect T-cell growth. In comparison to it, the excessive expression of LMO2 in CD34+ cells can cause ongoing increases in the development of T cells. Conversely, there is no effect on the development of B cells and myeloid cells. This information helps explain why LMO2 is mostly affected by various identified T-ALL oncogenes. In addition, throughout the process of T-cell development, expression of IL2R-gamma mediated by retrovirus may not always be oncogenic. As an alternative, replacement of signals of common IL-7 receptors may increase development of T cells wherever LMO2 was expressed and caused abnormal thymocyte development.
2015-06-16 | Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice.
Hematopoietic stem cell (HSC) gene therapy is a demonstrated effective treatment for X-linked severe combined immunodeficiency (SCID-X1), but B-cell reconstitution and function has been deficient in many of the gene therapy treated patients. Cytoreductive preconditioning is known to improve HSC engraftment, but in general it is not considered for SCID-X1 since the poor health of most of these patients at diagnosis and the risk of toxicity preclude the conditioning used in standard bone marrow stem cell transplantation. We hypothesized that mobilization of HSC by granulocyte colony-stimulating factor (G-CSF) should create temporary space in bone marrow niches to improve engraftment and thereby B-cell reconstitution. In the present pilot study supplementing our earlier preclinical evaluation (Huston et al., 2011), Il2rg(-/-) mice pretreated with G-CSF were transplanted with wild-type lineage negative (Lin(-)) cells or Il2rg(-/-) Lin(-) cells transduced with therapeutic IL2RG lentiviral vectors. Mice were monitored for reconstitution of lymphocyte populations, level of donor cell chimerism, and antibody responses as compared to 2 Gy total body irradiation (TBI), previously found effective in promoting B-cell reconstitution. The results demonstrate that G-CSF promotes B-cell reconstitution similar to low-dose TBI and provides proof of principle for an alternative approach to improve efficacy of gene therapy in SCID patients without adverse effects associated with cytoreductive conditioning.
2012-03-20 | IL-21 is the primary common γ chain-binding cytokine required for human B-cell differentiation in vivo.
SCID resulting from mutations in IL2RG or JAK3 is characterized by lack of T and natural killer cells; B cells are present in normal number, but antibody responses are defective. Hematopoietic cell transplantation (HCT) is curative for SCID. However, B-cell dysfunction persists in a substantial proportion of patients. We hypothesized that impaired B-cell responses after HCT in IL2RG/JAK3 deficiency results from poor donor B-cell engraftment and defective γc-dependent cytokine signaling in host B cells. To test this, and to identify which γc cytokine(s) is critical for humoral immunity, we studied 28 transplanted patients with IL2RG/JAK3 deficiency. Lack of donor B-cell engraftment associated with persistent humoral dysfunction and significantly reduced memory B cells. B-cell proliferation induced by CD40L alone or together with CpG, anti-Ig, IL-4, IL-10, or IL-13 was comparable in healthy controls and in post-HCT SCID patients, irrespective of their chimerism status. However, in vitro stimulation with CD40L/IL-21 induced B-cell proliferation, plasmablast differentiation, and antibody secretion in patients with donor B cells, but not in patients with autologous B cells. These data imply that IL-21-mediated signaling is critical for long-lived humoral immunity and to restore antibody responses in IL2RG/JAK3-deficient patients after HCT. Furthermore, in vitro stimulation with CD40L/IL-21 can predict in vivo B-cell immunity in IL2RG/JAK3 SCID after transplantation.
small molecules
2024-09-05 | Unrelated cord blood transplantation using minimal-intensity conditioning in a 1.5-month-old infant with X-linked severe combined immunodeficiency.
Severe combined immunodeficiency (SCID) is a heterogenous disorder with profound deficiency of T/B-cell functions. The best SCID therapy requires hematopoietic stem cell transplantation (HSCT) early in life. HSCT with conditioning is necessary to achieve a long-term reconstitution of B-cell functions. However, conditioning may aggravate pre-existing infection and cause transplant-related toxicity, especially in very young infants. Hence, the intensity of conditioning should be reduced to allow the reconstitution of immunity including B cells to the extent that prevents transplant-related toxicity and delayed complications. An infant with a family history of X-linked SCID (X-SCID) was diagnosed with X-SCID disorder soon after birth. The infant exhibited cytomegalovirus (CMV) infection despite being strictly isolated. At 1.5 months of age, we performed an unrelated cord blood transplantation (CBT) with a less intensity conditioning regimen: fludarabine (125 mg/m2) + melphalan (80 mg/m2). We evaluated the efficacy of reconstitution by assessing B-cell function and growth and psychomotor development at 5 years and 7 months after CBT. The clinical course after CBT was uneventful after CBT. The CMV infection was fully controlled by ganciclovir or foscavir therapy, which was discontinued at day 55 after CBT. Furthermore, immunoglobulin (Ig) replacement therapy was also discontinued at 6 months after CBT. A sufficient proportion of CD27+ memory B cells was developed, which was essential for an effective vaccination and prevention of infections. While the B-cell chimerism became recipient-dominant, the Ig replacement therapy was substituted by very successful post-vaccine immunity acquisition after CBT. The analysis of the general developmental parameters showed that chemotherapy did not cause any delay in growth and psychomotor development. The CBT therapy with this conditioning regimen was well tolerated and induced an effective reconstitution of B-cell functions in an X-SCID infant under the 3 months of age.
2022-02-03 | Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.
The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.
2021-06-22 | X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure.
We previously reported the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib improve outcomes in a mouse model of polymicrobial sepsis. Now we show that genetic deficiency of the BTK gene alone in Xid mice confers protection against cardiac, renal, and liver injury in polymicrobial sepsis and reduces hyperimmune stimulation ("cytokine storm") induced by an overwhelming bacterial infection. Protection is due in part to enhanced bacterial phagocytosis in vivo, changes in lipid metabolism and decreased activation of NF-κB and the NLRP3 inflammasome. The inactivation of BTK leads to reduced innate immune cell recruitment and a phenotypic switch from M1 to M2 macrophages, aiding in the resolution of sepsis. We have also found that BTK expression in humans is increased in the blood of septic non-survivors, while lower expression is associated with survival from sepsis. Importantly no further reduction in organ damage, cytokine production, or changes in plasma metabolites is seen in Xid mice treated with the BTK inhibitor ibrutinib, demonstrating that the protective effects of BTK inhibitors in polymicrobial sepsis are mediated solely by inhibition of BTK and not by off-target effects of this class of drugs.
2019-11-13 | The Common Cytokine Receptor γ Chain Family of Cytokines.
Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on their sharing the common cytokine receptor γ chain (γc), which was originally discovered as the third receptor component of the IL-2 receptor, IL-2Rγ. The IL2RG gene is located on the X chromosome and is mutated in humans with X-linked severe combined immunodeficiency (XSCID). The breadth of the defects in XSCID could not be explained solely by defects in IL-2 signaling, and it is now clear that γc is a shared receptor component of the six cytokines noted above, making XSCID a disease of defective cytokine signaling. Janus kinase (JAK)3 associates with γc, and JAK3-deficient SCID phenocopies XSCID, findings that served to stimulate the development of JAK3 inhibitors as immunosuppressants. γc family cytokines collectively control broad aspects of lymphocyte development, growth, differentiation, and survival, and these cytokines are clinically important, related to allergic and autoimmune diseases and cancer as well as immunodeficiency. In this review, we discuss the actions of these cytokines, their critical biological roles and signaling pathways, focusing mainly on JAK/STAT (signal transducers and activators of transcription) signaling, and how this information is now being used in clinical therapeutic efforts.
2019-09-16 | The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications.
The common cytokine receptor γ chain, γc, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γc results in X-linked severe combined immunodeficiency in humans, and γc family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.
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2021-11-02 | Case Report: Reactive Lymphohistiocytic Proliferation in Infant With a Novel Nonsense Variant of IL2RG Who Received BCG Vaccine
We present here a male young infant with X-linked severe combined immunodeficiency (MIM#300400) due to the novel nonsense variant of IL2RG (interleukin 2 receptor, gamma; MIM#308380), NM_000206.2( IL2RG ):c.820_823dup p.Ser275Asnfs * 29. He developed aggressive reactive lymphohistiocytic proliferation after receiving the live-attenuated Bacillus Calmette-Guérin (BCG) vaccine at birth. This report advocates for modifying the current practice of early use of BCG. The natural history of his disease also suggests considering IL2RG variants as a potential cause of “X-linked recessive Mendelian susceptibility to mycobacterial disease” (MSMD). His reactive lymphohistiocytic proliferation and massive hepatosplenomegaly simulated hemophagocytic lymphohistiocytosis (HLH, likely triggered by the BCG disease). This entity was masked by the absence of fever and markedly elevated inflammatory biomarkers. Thus, his findings stimulate discussion on the need to modify the diagnostic criteria of HLH, in order to accommodate conditions, such IL2RG variants that block systemic inflammation.
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Drug Discovery Landscape
2 orphan drug designations for T-B+ severe combined immunodeficiency due to gamma chain deficiency.
2 orphan drug designations for T-B+ severe combined immunodeficiency due to gamma chain deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
autologous CD34+ bone marrow derived stem cells transduced with a self-inactivating gammaretroviral vector encoding the human IL2RG (yc) | gene therapies | FDA | 2015-01-15 | — | Boston Children's Hospital |
retroviral gamma-c cDNA containing vector | gene therapies | FDA | 2002-04-29 | — | AVAX technologies, Inc. |
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