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.
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2025-08-02 | Innate-like memory T cells rapidly emerge in humans after gene therapy for SCID-X1.
Virtual memory T cells, possessing features of innate immune cells, represent a developmental continuum between innate and adaptive immunity. Here, we describe the genesis of virtual memory T cells during early human life. A longitudinal analysis of peripheral T cells after gene therapy for X-linked severe combined immunodeficiency (SCID-X1) in infants revealed an early enrichment of innate-like memory CD8+ T cells that expressed NKG2A, innate-associated transcriptional profiles, and a distinct T cell receptor (TCR) repertoire. Genome-wide DNA methylation profiling of the de novo innate-like memory NKG2A+ T cell subset confirmed a subset-specific epigenetic signature that included a poised effector response. Furthermore, ex vivo stimulation of NKG2A+ T cells with IL-12 and IL-18 resulted in antigen-independent interferon gamma (IFNγ) expression. Collectively, these data indicate that NKG2A+ innate-like memory T cells develop early in human life and are epigenetically poised to rapidly elicit effector cytokines in an antigen-independent manner.
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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.
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