cell therapies

2026-03-02 | Allogeneic hematopoietic cell transplantation for partial RAG deficiency in children and adults: Excellent outcomes with a reduced-intensity posttransplantation cyclophosphamide-based approach.

Partial recombinase activating gene deficiency (pRD) leads to combined immunodeficiency with immune dysregulation. It can be cured by allogeneic hematopoietic cell transplantation (HCT), but optimal referral criteria and approaches remain to be defined. Our study evaluated low-toxicity approaches to HCT for pRD. Thirteen children and adults with pRD received radiation-free, predominantly reduced-intensity conditioning (pentostatin/cyclophosphamide/busulfan) HCT with posttransplantation cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis at median (range) age 20 (4-46) years. With median 2.6 years' follow-up, overall survival for the entire cohort was estimated at 92% and 83% at 1 and 2 years and 100% and 90% for reduced-intensity conditioning recipients (n = 12), with 2 deaths attributed to sepsis. Reversal of clinical manifestations was associated with immune reconstitution, with minimal de novo autoimmunity, 15% 1-year cumulative incidence of grade III-IV acute GVHD, and no chronic GVHD. Vα7.2-positive T-cell proportion increased rapidly after HCT, while mucosa-associated invariant T-cell reconstitution lagged. Dysreactive CD19hiCD21lo and 9G4+ B cells decreased after HCT, along with clinically relevant autoantibodies. However, baseline elevated anti-type I interferon antibodies, potentially predisposing to severe viral infections, decreased slowly, although neutralizing activity was reduced at last follow-up. Outcomes did not differ by donor carrier status or HLA matching. Bronchiectasis exacerbations incurred rehospitalizations in long-term follow-up of patients who entered HCT with irreversible lung disease. Reduced-intensity conditioning HCT with posttransplantation cyclophosphamide-based GVHD prophylaxis is safe and effectively reverses immune dysfunction in patients with pRD.

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2026-02-03 | Durable hematopoiesis and tolerance after vertebral bone marrow transplant from a deceased lung transplant donor.

We hypothesized that bone marrow transplantation (BMT) using marrow extracted from the vertebral bodies (VBs) of an unrelated deceased lung transplant donor would be able to establish persistent hematopoiesis and generate immunity and tolerance. A teenager with severe combined immunodeficiency with lung failure due to recurrent pneumonias underwent lung transplantation in 2016 from a 1/8 HLA allele-matched unrelated donor, followed by BMT 4 months later using T cell/B cell-depleted, cryopreserved VB marrow. Rapid engraftment was followed by accelerating immune competence at 6 months, with independence from immunosuppression by 16 months. Donor T cell (>95%) and myeloid chimerism (7%-10%) has persisted for over 9 years. At 2 years after BMT, circulating T cells were hyporesponsive to host dendritic cells in vitro. T cell receptor clonotyping revealed the disappearance of host-reactive clones, and T cell RNA sequencing exhibited downmodulated signaling pathways for cytotoxicity/rejection, paired with upregulated immunomodulatory pathways, suggesting active suppression. In parallel, host monocytes upregulated certain signaling pathways, indicating active interactions between post-thymic donor T cells and host monocytes. In summary, for the first time to our knowledge, durable hematopoietic engraftment, immunity, and tolerance were demonstrable in a recipient of BMT obtained from a VB graft.

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2026-01-01 | Successful T-cell engraftment following unconditioned matched unrelated donor transplant in a child with Omenn syndrome and recurrent multidrug-resistant infections: A case report

Omenn syndrome is a rare form of severe combined immunodeficiency characterized by immune dysregulation, recurrent infections, erythroderma, eosinophilia, and failure to thrive. Hematopoietic stem cell transplantation (HSCT) remains the definitive treatment; however, outcomes are particularly challenging in patients with active severe infections before transplantation. Here, we report the case of a female infant who presented with persistent diarrhea and recurrent otitis media at 2 months of age and was diagnosed at 3 months with genetically confirmed Omenn syndrome caused by a homozygous pathogenic RAG1 variant (c.1187G>A; p.Arg396His). Her clinical course was complicated by recurrent multidrug-resistant bacterial bloodstream infections, Candida auris fungemia, acute kidney injury, disseminated intravascular coagulation, and respiratory failure requiring pediatric intensive care admission. Because she was clinically unstable for conventional conditioning chemotherapy, she underwent unconditioned matched unrelated donor peripheral blood stem cell transplantation at 8 months of age. Despite persistent mixed donor chimerism and absent B-cell engraftment, she demonstrated progressive donor-derived T-cell recovery, normalization of CD4/CD8 ratio, resolution of recurrent infections, and sustained clinical stability. To our knowledge, reports describing unconditioned matched unrelated donor HSCT in genetically confirmed Omenn syndrome complicated by multidrug-resistant bacterial infections and Candida auris fungemia remain extremely limited. This case highlights that unconditioned HSCT may provide clinically meaningful immune reconstitution when standard conditioning is not feasible.

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2025-12-15 | The T385M STAT1 gain-of-function mutation confers the most severe disease outcomes.

Gain-of-function (GOF) mutations in STAT1 cause a combined immunodeficiency characterized by chronic mucocutaneous candidiasis (CMC), recurrent infections, and autoimmunity. Mutations in the DNA-binding domain (DBD) have previously been associated with poor outcomes, but the contributions of specific variants to clinical phenotype remain unexplored. We performed a systematic literature review to identify patients with confirmed STAT1 GOF mutations, integrating new cases with a previously reported international cohort. Clinical and genetic data were analyzed at both domain and mutation level to define genotype-phenotype correlations. A total of 533 unique patients from 36 countries were identified, harboring 135 distinct mutations. As previously reported, DBD mutations were associated with increased risk of systemic infections, bronchiectasis, autoimmunity, and reduced survival. However, mutation-level stratification revealed that the T385M variant accounted for much of this effect. Compared with both other DBD mutations and mutations elsewhere in STAT1, T385M conferred significantly higher rates of infection, bronchiectasis, autoimmunity, and premature death (p < 0.001). Conversely, certain coiled-coil (CC) domain mutations, such as R274Q, were associated with milder disease and improved survival. Our findings demonstrate that the adverse prognosis previously ascribed to DBD mutations in STAT1 GOF is predominantly driven by the T385M variant. Mutation-specific, rather than domain-level, stratification is therefore essential for accurate risk assessment and clinical management. In particular, patients predicted to have severe disease, such as those with the T385M mutation should be considered early for curative interventional therapies such as stem cell transplant or gene therapy.

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2025-11-25 | Outcomes following matched sibling donor transplantation for severe combined immunodeficiency: a report from the PIDTC.

The Primary Immune Deficiency Treatment Consortium performed a retrospective analysis of 133 patients with severe combined immunodeficiency (SCID) receiving matched sibling donor (MSD) hematopoietic cell transplantation (HCT) between 1980 and 2023 at 30 North American institutions. In this largest cohort of MSD outcomes in patients with SCID to date, we examined the impact of conditioning regimen and graft-versus-host disease (GVHD) prophylaxis on survival and immune recovery. Outcomes after MSD HCT for SCID were excellent. Patients without an active infection or failure to thrive (FTT) at the time of HCT had 5-year overall survival superior to those with infection or FTT. Acute and chronic GVHD outcomes were independent of GVHD prophylaxis, conditioning regimen, SCID type, or presence of maternal engraftment. Patients without active infection at the time of HCT had superior chronic GVHD-free event-free survival vs those with infection. T-cell reconstitution at 6 months was less likely achieved with use of GVHD prophylaxis or serotherapy, and in patients with leaky SCID or Omenn syndrome. At 6 months, 1 year, and 2-5 years, T-cell reconstitution was less likely with ADA, DCLRE1C, or RAG genotype. B-cell reconstitution at 1 year and 2-5 years was negatively affected by development of grade 2 to 4 or 3 to 4 acute GVHD. Conditioning did not affect T- or B-cell reconstitution. Our data suggest omitting conditioning and GVHD prophylaxis for patients with typical SCID did not negatively affect 5-year outcomes after MSD HCT, but the data are insufficient to recommend this approach for best long-term outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.

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gene therapies

2026-04-13 | Restoration of the immune system with base editing and non-genotoxic conditioning in a Rag2 point-mutant mouse model.

Transplantation of donor hematopoietic stem and progenitor cells (HSPCs) is a well-established curative treatment for various blood and immune diseases, including severe combined immunodeficiency (SCID). However, it comes with significant toxicities, including graft-versus-host disease (GvHD) and tissue damage resulting from the use of genotoxic chemotherapy-containing conditioning regimens. Autologous transplantation using gene-modified HSPCs eliminates GvHD but currently still relies on genotoxic conditioning. Further, gene modification of HSPCs has commonly utilized integrating viruses, which carry the risk of oncogenesis. The ideal therapy would eliminate the risks associated with current hematopoietic stem cell (HSC) gene-modification and conditioning approaches. Here, we combined base editors (BEs), engineered virus-like particles (eVLPs), and non-genotoxic αCD117 antibody-drug conjugate (ADC) conditioning to explore optimal curative treatment of SCID. We generated a Rag2 SCID mouse model with a single point mutation (pm) and corresponding BE. Rag2pm/pm HSPCs were corrected using SpCas9NG-ABE-eVLPs without off-target effects being detected. Even in settings of low editing, transplantation of BE-corrected HSPCs into αCD117-ADC-conditioned mice led to efficient immune cell production in peripheral blood with normal B cell progenitors in the bone marrow. Combining αCD117-ADC conditioning with transplantation of HSPCs that were base edited using eVLPs successfully reversed the SCID phenotype in mice, showcasing a significant advancement in reducing treatment-related toxicities while enabling disease correction.

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2026-02-28 | CRISPR-Cas9-based gene editing as a proof-of-concept approach in an inborn error of immunity caused by a DCLRE1C variant.

Hypomorphic DCLRE1C variants impair T and B cell development, leading to combined immunodeficiency (CID) or leaky severe combined immunodeficiency (SCID). Current treatment options, such as allogeneic hematopoietic stem cell transplantation (aHSCT), are associated with significant risks, highlighting the need for alternative therapeutic strategies. In this study, we report the first a proof-of-concept CRISPR-Cas9–mediated correction of a hypomorphic DCLRE1C variant (c.194 C > T; p.T65I) in CD4 + helper T (Th) cells using CRISPR-Cas9 gene-editing technology. CD4 + Th cells were isolated, and the variant region was edited with sgRNA and donor DNA. Gene editing efficiency was confirmed by Sanger sequencing, revealing successful restoration of the target region to its wild-type sequence. Functional analyses showed a significant increase in CD25 activation and Artemis protein expression post-editing, although DCLRE1C mRNA levels remained unchanged. The approximately 6–8% increase in CD25 expression was statistically significant but did not reach healthy control levels. These findings suggest that CRISPR-Cas9 –mediated gene editing may enable precise correction and induce measurable cellular-level functional changes, supporting biological feasibility rather than therapeutic efficacy. This study provides a foundation for future research on HSCs and underscores the potential role of CRISPR-Cas9–based approaches in the treatment of inborn errors of immunity (IEIs) associated with DCLRE1C variants.

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2023-11-13 | Partial correction of immunodeficiency by lentiviral vector gene therapy in mouse models carrying Rag1 hypomorphic mutations

Introduction Recombination activating genes ( RAG ) 1 and 2 defects are the most frequent form of severe combined immunodeficiency (SCID). Patients with residual RAG activity have a spectrum of clinical manifestations ranging from Omenn syndrome to delayed-onset combined immunodeficiency, often associated with granulomas and/or autoimmunity (CID-G/AI). Lentiviral vector (LV) gene therapy (GT) has been proposed as an alternative treatment to the standard hematopoietic stem cell transplant and a clinical trial for RAG1 SCID patients recently started. However, GT in patients with hypomorphic RAG mutations poses additional risks, because of the residual endogenous RAG1 expression and the general state of immune dysregulation and associated inflammation. Methods In this study, we assessed the efficacy of GT in 2 hypomorphic Rag1 murine models (Rag1 F971L/F971L and Rag1 R972Q/R972Q ), exploiting the same LV used in the clinical trial encoding RAG1 under control of the MND promoter. Results and discussion Starting 6 weeks after transplant, GT-treated mice showed a decrease in proportion of myeloid cells and a concomitant increase of B, T and total white blood cells. However, counts remained lower than in mice transplanted with WT Lin- cells. At euthanasia, we observed a general redistribution of immune subsets in tissues, with the appearance of mature recirculating B cells in the bone marrow. In the thymus, we demonstrated correction of the block at double negative stage, with a modest improvement in the cortical/medullary ratio. Analysis of antigenspecific IgM and IgG serum levels after in vivo challenge showed an amelioration of antibody responses, suggesting that the partial immune correction could confer a clinical benefit. Notably, no overt signs of autoimmunity were detected, with B-cell activating factor decreasing to normal levels and autoantibodies remaining stable after GT. On the other hand, thymic enlargement was frequently observed, although not due to vector integration and insertional mutagenesis. In conclusion, our work shows that GT could partially alleviate the combined immunodeficiency of hypomorphic RAG1 patients and that extensive efficacy and safety studies with alternative models are required before commencing RAG gene therapy in thesehighly complex patients.

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2023-07-28 | The recombinase activating genes: architects of immune diversity during lymphocyte development.

The mature lymphocyte population of a healthy individual has the remarkable ability to recognise an immense variety of antigens. Instead of encoding a unique gene for each potential antigen receptor, evolution has used gene rearrangements, also known as variable, diversity, and joining gene segment (V(D)J) recombination. This process is critical for lymphocyte development and relies on recombination-activating genes-1 (RAG1) and RAG2, here collectively referred to as RAG. RAG serves as powerful genome editing tools for lymphocytes and is strictly regulated to prevent dysregulation. However, in the case of dysregulation, RAG has been implicated in cases of cancer, autoimmunity and severe combined immunodeficiency (SCID). This review examines functional protein domains and motifs of RAG, describes advances in our understanding of the function and (dys)regulation of RAG, discuss new therapeutic options, such as gene therapy, for RAG deficiencies, and explore in vitro and in vivo methods for determining RAG activity and target specificity.

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2022-12-28 | Lentiviral Gene Therapy for Artemis-Deficient SCID.

The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in DCLRE1C, which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation. We carried out a phase 1-2 clinical study of the transfusion of autologous CD34+ cells, transfected with a lentiviral vector containing DCLRE1C, in 10 infants with newly diagnosed ART-SCID. We followed them for a median of 31.2 months. Marrow harvest, busulfan conditioning, and lentiviral-transduced CD34+ cell infusion produced the expected grade 3 or 4 adverse events. All the procedures met prespecified criteria for feasibility at 42 days after infusion. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all the patients. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. The diversity of T-cell receptor β chains normalized by 6 to 12 months. Four patients who were followed for at least 24 months had sufficient B-cell numbers, IgM concentration, or IgM isohemagglutinin titers to permit discontinuation of IgG infusions. Three of these 4 patients had normal immunization responses, and the fourth has started immunizations. Vector insertion sites showed no evidence of clonal expansion. One patient who presented with cytomegalovirus infection received a second infusion of gene-corrected cells to achieve T-cell immunity sufficient for viral clearance. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this condition resolved after reconstitution of T-cell immunity. All 10 patients were healthy at the time of this report. Infusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID resulted in genetically corrected and functional T and B cells. (Funded by the California Institute for Regenerative Medicine and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03538899.).

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antibodies

2026-05-01 | A60-16 Clinical Phenotypes and Therapeutic Exploration of 10 Cases of Inborn Errors of Immunity With Prominent Allergic Manifestations

Abstract Objective Inborn errors of immunity (IEI) are often associated with recurrent infections, autoimmunity, autoinflammation, malignancies, and allergic diseases. IEI cases presenting predominantly with allergies are rarely reported, leading to diagnostic challenges. This study reports the genotypes, clinical features, and treatment outcomes of 10 pediatric IEI patients with primarily allergic manifestations to improve awareness and clinical management. Methods Clinical data, whole-exome sequencing, treatment details, and follow-up information of 10 pediatric patients (2019-2025) were analyzed retrospectively. Results 1. Patient ages ranged from 3 months to 14 years (6 males, 4 females). Diagnoses included WAS (1), high IgE syndrome (4), Omenn syndrome (2), FLG gene mutation (1), chromosomal duplication with FLG mutation (1), and isolated chromosomal duplication (1). Mutated genes included WAS, STAT3, SPINK5, DOCK8, RAG1, and FLG. Two patients had chromosomal abnormalities. 2.All patients primarily presented with allergic symptoms. Except for one DOCK8 mutation and one FLG mutation with onset at age 8, all others developed symptoms in the neonatal period. The most common manifestations were eczema (5/10) and atopic dermatitis (5/10), followed by food allergies and allergic rhinitis. Most patients experienced wheezing or recurrent respiratory infections. Three cases presented with bronchiectasis or chronic infectious pneumonia. Three patients developed erythroderma. They experienced severe pruritus, engaging in incessant scratching during waking hours, with minimal relief from conventional antihistamines. Notably, one DOCK8 mutation case combined with uveitis, representing the first reported complication associated with DOCK8 variation. All patients showed markedly elevated total IgE levels, with five exceeding 1000 kU/L. Nine out of ten had elevated eosinophil counts; in one case, peripheral blood eosinophils rose to 55 after dupilumab treatment. Skin biopsies in three patients confirmed recurrent infections with pathogens including Staphylococcus aureus, Candida albicans, and Epstein-Barr virus.3. Conventional antihistamines were ineffective for pruritus. Prior to biologics, treatment often involved corticosteroids and intravenous immunoglobulin, with recurrent or persistent dermatitis. Biologics like dupilumab showed significant improvement in dermatitis and pruritus, especially in patients with DOCK8, SPINK5, and FLG mutations. One DOCK8 patient with uveitis improved with adalimumab. A patient with chromosome 3 duplication responded to tofacitinib, while one SPINK5 patient had better results with secukinumab after a recurrence on dupilumab. One Omenn syndrome patient died from severe infection. Conclusions 1. Allergic diseases are common in children, but early-onset, refractory allergic conditions warrant vigilance for IEI. 2. Biologics may help improve allergic symptoms in these patients. This abstract is funded by: None

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2026-05-01 | Dominant-Negative FOXN1 Mutations: Clinical Variability and Omenn Syndrome Management in an International Cohort of 7 Families

Background Transcription factor forkhead box protein N1 (FOXN1) is the master transcription factor required for differentiation and maintenance of thymic epithelial cells (TECs) and is not only required for embryonic thymus development but also for postnatal thymic maintenance. Autosomal recessive FOXN1 deficiency leads to alopecia, nail dystrophy, and nude severe combined immune deficiency (SCID) due to athymia requiring thymus transplantation. Dominant-negative (DN) heterozygous variants, on the other hand, have incomplete and highly variable phenotypes. We hereby present an international cohort of families carrying dominant-negative mutations with variable clinical presentation, course, and outcomes. Methods Patient medical records and diagnosing physicians were consulted. Results We present 15 FOXN1 DN heterozygotes from 7 different families across the world, demonstrating highly variable intrafamilial clinical courses and management. Age at diagnosis ranged from 0.2 to 45 years. Eight patients were male, and seven were female. Four individuals were diagnosed through newborn screening (NBS) for SCID. Immunological phenotype included Omenn syndrome (OS) (6/15), SCID-like disease (1/15), combined immunodeficiency (CID) with autoimmunity complications (1/15), T cell lymphopenia (5/15) or antibody deficiency (2/15), and one asymptomatic individual. Herpesviridae-related complications were prominent, including EBV viremia (3/15), Varicella pneumonia (1/15), severe Varicella infection (1/15), and CMV disease (3/15), one of which presented with CMV retinitis. The severity and management of OS were variable: one patient was managed with monitoring alone, one received immunoglobulin replacement therapy (IgRT) alone, one received antimicrobial therapy only, two received IgRT and antimicrobial prophylaxis, and one was treated with prednisone, cyclosporine, IgRT, and broad antimicrobial prophylaxis. One patient underwent hematopoietic stem cell transplantation (HSCT) before the identification of DN-FOXN1 and died from transplant-related complications. No OS patient required HSCT. Up to date, no patient has received a thymic transplant. Conclusions Heterozygous FOXN1 variants have traditionally been considered mild, with immune function often improving over time and without the need for definitive therapies. However, DN-FOXN1 variants appear to carry a broader clinical spectrum, including OS. In our cohort, OS manifestations were variable and could often be managed with supportive care, including IgRT, antimicrobial prophylaxis, and, when indicated, immunosuppression, and none of the patients has required thymic transplantation to date.

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2025-12-22 | Clinical Variance in an International Cohort of Families with Dominant-Negative FOXN1 Mutations

Introduction Transcription factor Forkhead box protein N1 (FOXN1) regulates thymic epithelial cell development. Bi-allelic and compound heterozygote loss-of-function mutations result in nude-severe combined immune deficiency with athymia, alopecia, and nail dystrophy requiring thymus transplantation. Dominant-negative heterozygous variants have incomplete and highly variable phenotypes. We present an international cohort of families carrying dominant negative mutations with variable clinical presentation, course, and outcomes. Methods Patient medical records and diagnosing physicians were consulted. Results We have access to 11 FOXN1 dominant-negative heterozygotes from 4 families with highly variable intrafamilial clinical courses and management. All variants locate near the C terminus, like variants in Rota et al. [1]. Immunological phenotype included 5/11 with Omenn syndrome (OS) early in life, otherwise presenting as asymptomatic (2/11) or with T cell lymphopenia (4/11), characterized by persistently low naïve T cells, and specific antibody deficiency (1/11) even in middle age. Alopecia and/or nail dystrophy was only noted in 1/11 patients. OS treatments ranged from conservative management (1/5), short-term steroids (1/5), long-term prednisolone alone (1/5), cyclosporine and prednisolone (1/5), and 1/5 OS patients received a bone marrow transplant prior to genetic diagnosis and later expired. (3/11) patients were placed on immunoglobulin replacement therapy. Only 3/11 patients experienced adverse outcomes, with 1/11 deaths. Other adverse outcomes include severe herpesviridae infections: Varicella pneumonia and CMV retinitis, respectively. 2/11 patients experienced EBV viremia and 2/11 with CMV viremia. 1/2 families tested were positive for anti-IFNα autoantibodies. Only one patient is being considered for thymic transplant. Conclusions This cohort demonstrates intrafamilial variability ranging from asymptomatic symptoms to OS, which has seldom been described in athymia patients. Heterogeneity indicates a need for distinct longitudinal treatment protocols for dominant negative FOXN1 patients, including lifelong protective immunoglobulin replacement therapy, and the possibility of thymic transplant for best outcomes, which has not been performed in FOXN1 heterozygotes before.

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2025-10-27 | Rubella-associated granuloma in a patient with a compound heterozygous RAG1 defect and review of the literature.

Recombination-activating gene (RAG) 1-2 deficiencies have a phenotype spectrum from severe combined to combined immunodeficiency (CID). We presented a comprehensive immunologic/genetic/radiologic/pathological, and virologic evaluation results of a patient with granuloma and reviewed the medical literature in 2022-2025 period for rubella virus (RuV)-associated granulomas in inborn errors of immunity (IEI). We evaluated a 17-year-old male patient with a necrotic, ulcerated, and exudative lesion extending over the right foot and leg at the edge of amputation. He had a history of recurrent pneumonia and bronchiectasis. Further evaluation revealed systemic granulomas (skin, spleen) in addition to the extremity lesions and low T- and B-, and naive CD4 + T cell numbers. In addition to a defined heterozygous RAG1 mutation(c.1421 G > A, R474H) detected with NGS PID-panel analysis, Sanger sequencing analysis confirmed patient`s CID diagnosis by revealing another heterozygous mutation(c.1181 G > A, R394Q). Histopathology demonstrated necrotizing granulomas with vasculitis and RT-PCR study from the splenic granulomas revealed RuV. The ulceration and exudative extremity lesions regressed with a scar within two months after the initiation of the anti-TNF therapy. In addition to CID therapy, hematopoietic stem cell transplantation was planned from his HLA-matched sibling donor. RuV-associated granuloma usually develop in the first 12 years and accompany gene defects related to Griscelli disease and familial hemophagocytic lymphohistiocytosis (HLH) in the medical literature. Early, comprehensive diagnostic workup for granuloma could further reveal the RuV's role in granulomatous inflammation in IEI, leading to targeted therapy to improve outcomes. Thorough genetic investigation in the presence of granuloma is crucial.

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2025-10-20 | Atopic dermatitis in inborn errors of immunity: at the interface of immunodeficiency and immune dysregulation.

Inborn errors of immunity (IEI) encompass a broad spectrum of immunodeficiency disorders characterized by variability in genetic background, individual immunophenotype, and clinical manifestations with organ-specific immunopathology and immune dysregulation in the form of atopy, autoimmunity, polyclonal lymphoproliferation, and malignancy. With the ever-expanding insight in the pathophysiology of IEI, atopy may be perceived as an integral part and even a hallmark of IEI diseases. This review is aimed at gathering, delineating, and summarizing the immunogenetic underpinnings of IEI diseases accompanied by atopic dermatitis. Particular emphasis is laid on syndromes connected with atopy, such as hyper-IgE syndromes, Omenn syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, Netherton syndrome, Wiskott-Aldrich syndrome, and atypical complete DiGeorge syndrome. Therefore, atopic dermatitis proved not to be a sole disease, but rather a warning sign of multiple pediatric monogenic immunodeficiency disorders. Surpassing from the era of clinical and immunological diagnosis to the era of immunogenetics and the integrated "omics" approach highlighted the complex and heterogeneous immunopathology of atopic dermatitis. It also paved the way for patient-tailored immunotherapies with monoclonal antibodies and small molecules targeted at suppressing atopic inflammatory processes and improving disease-associated outcomes.

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small molecules

2026-07-14 | Evolution of Diagnosis and Management of Omenn Syndrome Using Multiple Immunosuppressive Strategies: A Case Series

Rationale Omenn syndrome represents a therapeutic challenge as a state of florid immune dysregulation born out of autoreactive oligoclonal T cells due to hypomorphic variants in genes associated with severe combined immunodeficiency (SCID). In the era of newborn screening, patients with Omenn SCID are often identified earlier in the disease course with a more subtle clinical presentation than is classically taught. With appropriate screening and subsequent management, outcomes of Omenn syndrome may be improved. Methods We analyzed the patients diagnosed with Omenn syndrome at the Children’s Hospital of Philadelphia from 2007 to 2025 (n = 7). Data collected included initial presenting signs and symptoms, laboratory features at diagnosis and over time, and management strategy. Results The patients in this series were diagnosed with Omenn syndrome at a median age of 9 days (interquartile range [IQR] 7-12) and were 57% female, and six had RAG1-associated SCID (86%). Frequent signs at diagnosis included rash (100%), lymphadenopathy (43%), and hepatomegaly and/or splenomegaly (43%). Common laboratory features at diagnosis were greater than 80% of CD4 T cells with memory phenotype (100%), eosinophilia (86%), elevated IgE (71%), abnormal T cell receptor excision circles (TREC; 100%), and oligoclonal T cells (14%, only 1 patient with T cell receptor vβ repertoire analysis pre-transplant). Maternal engraftment was negative in the six patients for whom it was tested; the only patient not tested was born in 2009. All patients were treated with systemic corticosteroids, 86% with tacrolimus, 29% with cyclosporine, and 29% with antithymocyte globulin. Median age at transplant was 90 days (IQR 73-94). The median time from Omenn syndrome presentation to transplant was 70 days (IQR 64-82). Conclusion We describe seven patients with Omenn syndrome diagnosed and managed early in life at a single center. Patients demonstrated the characteristic clinical and laboratory findings consistent with Omenn syndrome, with all presenting with a rash and nearly half with lymphadenopathy and hepatomegaly and/or splenomegaly. Most patients had eosinophilia and elevated IgE levels, and all patients had abnormal TREC results and greater than 80% of CD4 T cells with memory phenotype. The majority were successfully managed with systemic corticosteroids and tacrolimus alone, without the need for cyclosporine or antithymocyte globulin. Early diagnosis of Omenn syndrome facilitated timely initiation of targeted therapy and progression to hematopoietic stem cell transplantation within the first three months of life.

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2026-04-10 | Treosulfan-fludarabine conditioning in infants with severe combined immunodeficiencies: Extended study of the UK paediatric treosulfan study.

Allogeneic haematopoietic stem cell transplantation (HSCT) is a curative therapy for severe combined immunodeficiency (SCID). Conditioning improves donor engraftment and freedom from immunoglobulin replacement (IgR) but increases the risks of acute and late toxicity. Treosulfan, a reduced toxicity alkylating agent, has emerged as an alternative to busulfan. In this UK multicentre study, we evaluated outcomes of 104 infants with SCID who underwent first HSCT following treosulfan-fludarabine conditioning between 2006 and 2022. After a median follow-up of 5.4 years, 5-year overall survival (OS) and event-free survivals (EFS) were 81% and 77% respectively. On multivariate analysis, molecularly undefined SCID (OS hazard ratio [HR] 5.61; EFS HR 5.55) and pre-HSCT cytomegalovirus (CMV) infection (OS HR 3.94; EFS 3.68) were independently associated with inferior OS and EFS; RAG-DCLRE1C genotypes also predicted worse EFS (HR 4.35). Cumulative incidence of endothelial cell dysfunction (ECD) was 11%. Treosulfan dose was not associated with OS, EFS, ECD or donor myeloid chimerism. Low mixed donor myeloid chimerism was observed across all treosulfan doses, but IgR freedom was achieved in 92% of survivors after first HSCT. Treosulfan-fludarabine provides excellent survival with low endothelial toxicity for SCID HSCT, with potential for optimisation via pharmacokinetic guided dosing.

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2026-01-01 | CD3ε gene variant causing typical SCID and Omenn syndrome in patients from two unrelated families

Severe combined immune deficiencies (SCIDs) are a group of rare diseases that impact the immune system. Depending on the underlying gene defects, SCIDs exhibit various clinical and immunological phenotypes. Multiple gene defects have been linked to the presentation of SCIDs, including typical SCIDs and Omenn syndrome. Typical SCIDs manifest early in life with recurrent infections caused by opportunistic pathogens. Omenn syndrome is characterized by a clinical triad of erythroderma, hepatosplenomegaly, and lymphadenopathy, commonly accompanied by peripheral eosinophilia and elevated IgE levels. Here, we present two unrelated families (2 siblings & one patient from a different family), all of the same ethnicity and race, who presented with variable clinical and laboratory presentations of severe combined immunodeficiency (SCID) while harboring the same missense, homozygous variant in the CD3ε gene (P.Gly94Ala), previously classified as a variant of unknown significance. Our case series shows a potentially disease-causing variant that was previously classified as a variant of unknown significance, in addition to suggesting a treatment for Omenn syndrome-related immune dysregulation using corticosteroids as a monotherapy. We concluded that a defect in the CD3ε gene can result in classical SCID, along with features of Omenn syndrome that may arise from this genetic defect. A heightened level of suspicion is crucial for diagnosing SCID cases, as various presentations can emerge from the same genetic variant.

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2024-07-29 | Association of busulfan exposure and outcomes after HCT for patients with an inborn error of immunity.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment strategy for patients with inborn errors of immunities (IEIs). The objective of this study was to assess the optimal busulfan exposure before allogeneic HCT for patients with an IEI who received an IV busulfan-based conditioning regimen. Patients from 17 international centers were included. The main outcome of interest was event-free survival (EFS). Patients were categorized into 4 IEI subgroups: combined immunodeficiency (CID), severe combined immunodeficiency (SCID), neutrophil disorders, and hemophagocytic lymphohistiocytosis (HLH)-related disorders. Busulfan exposure was calculated by individual centers (area under the curve [AUC]CENTER) and re-estimated using a nonlinear mixed-effects model (NONMEM; exposure defined as AUCNONMEM). Overall, 562 patients were included: 173 (30.8%) with CID, 154 (27.4%) with SCID, 101 (18.0%) with HLH-related disorders, and 134 (23.8%) with neutrophil disorders. The median busulfan AUCNONMEM was 69.0 mg × h/L and correlated poorly with the AUCCENTER (r2 = 0.54). In patients with SCID, HLH-related, and neutrophil disorders with a busulfan AUCNONMEM of 70 to 90 mg × h/L, 2-year EFS was superior to <70 mg × h/L, and >90 mg ×h/L. Full donor chimerism increased with higher busulfan AUCNONMEM, plateauing at 90 mg × h/L. For patients with CID, the optimal AUCNONMEM for donor chimerism was found to be >70 mg × h/L. Improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUCNONMEM of 80 mg × h/L (range, 70-90). Our study stresses the importance of uniformly using a validated population pharmacokinetic model to estimate AUCNONMEM.

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2024-04-08 | Rapamycin Controls Lymphoproliferation and Reverses T-Cell Responses in a Patient with a Novel STIM1 Loss-of-Function Deletion.

Deficiency of stromal interaction molecule 1 (STIM1) results in combined immunodeficiency accompanied by extra-immunological findings like enamel defects and myopathy. We here studied a patient with a STIM1 loss-of-function mutation who presented with severe lymphoproliferation. We sought to explore the efficacy of the mTOR inhibitor rapamycin in controlling disease manifestations and reversing aberrant T-cell subsets and functions, which has never been used previously in this disorder. Clinical findings of the patient were collected over time. We performed immunological evaluations before and after initiation of rapamycin treatment, including detailed lymphocyte subset analyses, alterations in frequencies of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes as well as T cell activation and proliferation capacities. A novel homozygous exon 2 deletion in STIM1 was detected in a 3-year-old girl with severe lymphoproliferation, recurrent infections, myopathy, iris hypoplasia, and enamel hypoplasia. Lymphoproliferation was associated with severe T-cell infiltrates. The deletion resulted in a complete loss of protein expression, associated with a lack of store-operated calcium entry response, defective T-cell activation, proliferation, and cytokine production. Interestingly, patient blood contained fewer cTFH and increased circulating follicular regulatory (cTFR) cells. Abnormal skewing towards TH2-like responses in certain T-cell subpopulations like cTFH, non-cTFH memory T-helper, and Treg cells was associated with increased eosinophil numbers and serum IgE levels. Treatment with rapamycin controlled lymphoproliferation, improved T-cell activation and proliferation capacities, reversed T-cell responses, and repressed high IgE levels and eosinophilia. This study enhances our understanding of STIM1 deficiency by uncovering additional abnormal T-cell responses, and reveals for the first time the potential therapeutic utility of rapamycin for this disorder.

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2025-10-01 | Omenn Syndrome: Case of Severe Combined Immune Deficiency

Abstract Omenn syndrome (OS) is a rare form of severe combined immunodeficiency (SCID) with susceptibility to serious infections of the skin, lungs, joints, and septicemia. It is characterized by erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly, associated with SCID. These patients also suffer from opportunistic infections, including ear infections, recurrent pneumonitis due to Pneumocystis jiroveci, or to viruses such as cytomegalovirus, adenovirus or parainfluenza virus, and profuse oral candidiasis. The majority of mutations causing this condition are missense mutations in recombinase-activating genes, namely RAG1 and RAG 2. We report a case of 4-month-old female baby with a history of repeated bacterial, viral, and fungal infections since birth and failure to thrive. She was treated with antibiotics and antifungal for her recurrent infections. Investigations revealed the diagnosis of SCID. Further genetic studies showed RAG 1 gene mutation, thus confirming OS. The baby, however, succumbed to severe sepsis with shock during her third admission.

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2023-12-16 | Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome.

The DNA polymerase δ complex (PolD), comprising catalytic subunit POLD1 and accessory subunits POLD2, POLD3, and POLD4, is essential for DNA synthesis and is central to genome integrity. We identified, by whole exome sequencing, a homozygous missense mutation (c.1118A > C; p.K373T) in POLD3 in a patient with Omenn syndrome. The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination. The patient received hematopoietic stem cell transplantation at age 6 months. He manifested progressive neurological regression and ultimately died at age 4 years. We performed molecular and functional analysis of the mutant POLD3 and assessed cell cycle progression as well as replication-associated DNA damage. Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components. The cell cycle defect was rescued by transduction with WT POLD3. This study validates autosomal recessive POLD3 deficiency as a novel cause of profound T-cell deficiency and Omenn syndrome.

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2023-11-24 | Embryonic lymphocytes contribute to a genetic form of autoimmune inflammation

Abstract Omenn Syndrome (OS) is a rare hematological disorder, caused by hypomorphic mutations in genes involved in B-/T-cell receptor (BCR/TCR) rearrangement that result in impaired lymphocyte development and immunodeficiency. Notwithstanding, few T-cell clones enriched in self-reactive specificities expand in peripheral tissues, where they trigger severe inflammation and autoimmune reactions. Interestingly, residual OS lymphocytes display characteristics proper of embryonic lymphocytes that emerge before, and independently from, hematopoietic stem cells (HSCs). This prompted us to hypothesize whether OS autoreactive T-cells are generated in the embryo independently from HSCs. Here we show that in the Rag2 R229Q/R229Q OS mouse model, embryonic but not adult bone marrow-derived hematopoietic progenitors can generate T-cells. T-lymphopoiesis can be rescued in adult OS blood progenitors via their Lin28-mediated reprogramming to an embryonic-like state. Remarkably, when transplanted in immunodeficient mice, embryonic-like OS progenitors trigger tissue morphological alterations and inflammation in the large intestine of the recipients, recapitulating the typical OS inflammatory phenotype. Our study describes the previously unappreciated contribution of embryonic progenitors to the pool of autoreactive infilitrating T-cells, providing a novel platform for both the detailed study of human autoimmune disorders and the design of more targeted therapies.

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2023-07-23 | Immunological assessment of a patient with Omenn syndrome resulting from compound heterozygous mutations in the RAG1 gene.

The recombination activating gene 1 (RAG1) is essential for V(D)J recombination during T- and B-cell development. In this study, we presented a case study of a 41-day-old female infant who exhibited symptoms of generalized erythroderma, lymphadenopathy, hepatosplenomegaly, and recurrent infections including suppurative meningitis and septicemia. The patient showed a T+B-NK+ immunophenotype. We observed an impaired thymic output, as indicated by reduced levels of naive T cells and sjTRECs, coupled with a restricted TCR repertoire. Additionally, T-cell CFSE proliferation was impaired, indicating a suboptimal T-cell response. Notably, our data further revealed that T cells were in an activated state. Genetic analysis revealed a previously reported compound heterozygous mutation (c. 1186C > T, p. R396C; c. 1210C > T, p. R404W) in the RAG1 gene. Structural analysis of RAG1 suggested that the R396C mutation might lead to the loss of hydrogen bonds with neighboring amino acids. These findings contribute to our understanding of RAG1 deficiency and may have implications for the development of novel therapies for patients with this condition.

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2023-07-21 | Immune Responses 6 Months After mRNA-1273 COVID-19 Vaccination and the Effect of a Third Vaccination in Patients with Inborn Errors of Immunity.

Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID). In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (N = 18), combined immunodeficiency (CID) (N = 22), CVID (N = 203), isolated or undefined antibody deficiencies (N = 204), and phagocyte defects (N = 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed. At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines. A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.

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