RARE DISEASE
X-linked lymphoproliferative disease
X-linked lymphoproliferative disease
X-linked lymphoproliferative disease
Synonyms: Duncan disease, Purtilo syndrome, XLP
Synonyms: Duncan disease, Purtilo syndrome, XLP
Synonyms: Duncan disease, Purtilo syndrome, XLP
Drug discovery
192
papers
On emerging therapies
Overview
X-linked lymphoproliferative disease (XLP) is a rare X-linked recessive immunodeficiency caused by mutations in SH2D1A (XLP1) or XIAP (XLP2). It primarily affects males, leading to dysregulated immune responses, particularly to Epstein-Barr virus (EBV), and manifests as hemophagocytic lymphohistiocytosis (HLH), fulminant hepatitis, lymphoma, or hypogammaglobulinemia. Diagnosis involves genetic testing and protein expression analysis. Hematopoietic stem cell transplantation (HSCT) is curative, while acute management includes immunomodulators, chemotherapy, and EBV-targeted therapies [1][3][13][17].
Therapies
Curative: Allogeneic HSCT (preferably pre-EBV exposure) [3][9][17].
Acute management: HLH-94/04 protocols (e.g., dexamethasone, etoposide), rituximab, IVIG, and immunosuppressants [2][11][17].
Supportive: Immunoglobulin replacement for hypogammaglobulinemia; lymphoma-directed chemotherapy [3][7][18].
Categories: rare genetic diseases, rare immunological diseases
Research Papers
192 drug discovery papers about X-linked lymphoproliferative disease. Recent publications:
192 drug discovery papers about X-linked lymphoproliferative disease. Recent publications:
categories:
Small molecules
proteins
2026-01-16 | Acquired nonpermissive BM microenvironment impairs HSC proliferation and maintenance, and B-cell development after HSCT.
Defects in B-cell reconstitution upon hematopoietic stem cell (HSC) transplant (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective, and complete B-cell deficiency in the context of full donor chimerism in a patient with X-linked lymphoproliferative disease, and aimed to identify the contribution of the BM microenvironment in disrupted B-cell reconstitution after HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the BM of the index patient, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy HSCs, which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients' MSCs, and a progressive loss of CXCL12 expression. Indeed, survival of the patients' HSCs improved upon supplementing the in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent nonpermissive state for normal B-cell development.
2025-07-08 | X-linked lymphoproliferative syndrome type 1 presenting as DRESS-HLH overlap syndrome.
A preadolescent male, born to 3rd-degree consanguineous parents, presented with persistent fever, cough and dyspnoea. He had non-resolving suppurative otitis media and two episodes of pneumonia in the past 2 years. During admission, clinical and radiological evaluations revealed bilateral lung consolidation with synpneumonic effusion. Examination also revealed the absence of bilateral tonsils. Blood and pleural fluid cultures were sterile. The child developed a drug reaction with eosinophilia and systemic symptoms (DRESS) associated with haemophagocytic-lymphohistiocytic syndrome (HLH) during the hospital stay. Given his history of recurrent infections and absent tonsils, primary immunodeficiency disorder was suspected. Immunological work-up showed reduced levels of IgG and IgM in serum. Exome sequencing identified a mutation in the SH2D1A gene confirming a diagnosis of X-linked lymphoproliferative syndrome (Duncan syndrome). The child was started on regular intravenous immunoglobulin therapy, along with bacterial and fungal prophylaxis. His parents were counselled regarding the prognosis and necessity of haematopoietic stem cell transplantation as the definitive treatment.
2024-09-23 | Lentiviral vectors for precise expression to treat X-linked lymphoproliferative disease.
X-linked lymphoproliferative disease (XLP1) results from SH2D1A gene mutations affecting the SLAM-associated protein (SAP). A regulated lentiviral vector (LV), XLP-SMART LV, designed to express SAP at therapeutic levels in T, NK, and NKT cells, is crucial for effective gene therapy. We experimentally identified 34 genomic regulatory elements of the SH2D1A gene and designed XLP-SMART LVs to emulate the lineage and stage-specific control of SAP. We screened them for their on-target enhancer activity in T, NK, and NKT cells and their off-target enhancer activity in B cell and myeloid populations. In combination, three enhancer elements increased SAP promoter expression up to 4-fold in on-target populations in vitro. NSG-Tg(Hu-IL15) xenograft studies with XLP-SMART LVs demonstrated up to 7-fold greater expression in on-target cells over a control EFS-LV, with no off-target expression. The XLP-SMART LVs exhibited stage-specific T and NK cell expression in peripheral blood, bone marrow, spleen, and thymic tissues (mimicking expression patterns of SAP). Transduction of XLP1 patient CD8+ T cells or BM CD34+ cells with XLP-SMART LVs restored restimulation-induced cell death and NK cytotoxicity to wild-type levels, respectively. These data demonstrate that it is feasible to create a lineage and stage-specific LV to restore the XLP1 phenotype by gene therapy.
2021-12-23 | Epstein-Barr virus (EBV) hyperimmune globulin isolated from donors with high gp350 antibody titers protect humanized mice from challenge with EBV.
Primary infection with Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease and severe disease in patients with X-linked lymphoproliferative disease; no therapies are approved to prevent EBV infection in these patients. Hyperimmune globulin has been used to prevent some virus infections in immunocompromised persons. Here, we identified plasma donors with high titers of EBV gp350 and EBV B cell neutralizing antibodies. Pooled IgG isolated from these donors was compared to intravenous immunoglobulin (IVIG) for its ability to reduce viral load in the blood in humanized mice challenged with EBV. Mice that received EBV hyperimmune globulin had significantly reduced EBV DNA copy numbers compared to animals that received saline control; however, while animals that received EBV hyperimmune globulin had lower EBV DNA copies than those that received IVIG, the difference was not significant. Thus, while EBV hyperimmune globulin reduced viral load compared to IVIG, the effect was modest.
2019-05-13 | FOXP3 renders activated human regulatory T cells resistant to restimulation-induced cell death by suppressing SAP expression.
Restimulation-induced cell death (RICD) is an apoptotic program that regulates effector T cell expansion, triggered by repeated stimulation through the T cell receptor (TCR) in the presence of interleukin-2 (IL-2). Although CD4+ regulatory T cells (Tregs) consume IL-2 and experience frequent TCR stimulation, they are highly resistant to RICD. Resistance in Tregs is dependent on the forkhead box P3 (FOXP3) transcription factor, although the mechanism remains unclear. T cells from patients with X-linked lymphoproliferative disease (XLP-1), that lack the adaptor molecule SLAM-associated protein (SAP), are also resistant to RICD. Here we demonstrate that normal Tregs express very low levels of SAP compared to conventional T cells. FOXP3 reduces SAP expression by directly binding to and repressing the SH2D1A (SAP) promoter. Indeed, ectopic SAP expression restores RICD sensitivity in human FOXP3+ Tregs. Our findings illuminate the mechanism behind FOXP3-mediated RICD resistance in Tregs, providing new insight into their long-term persistence.
small molecules
2025-08-18 | Attenuation of NF-κB/NLRP3 inflammasome axis and oxidative stress, and upregulation of Nrf2/HO-1 signaling mediate the protective effect of S-carboxymethylcysteine against cyclophosphamide-induced cardiotoxicity.
Cyclophosphamide (CP) is a potent chemotherapeutic and immunosuppressant agent used in the management of lymphoproliferative disorders and solid tumors. However, it induces cardiotoxicity and other severe adverse effects, thereby limiting its clinical application, highlighting the need for safe and effective cardioprotective agents. This study investigates the cardioprotective potential of carbocysteine (S-carboxymethylcysteine (SCMC)), a mucolytic agent with emerging pleiotropic properties, against CP-induced toxicity. The study explores the effect of SCMC on oxidative stress, NF-κB/NLRP3 inflammasome axis and Nrf2/HO-1 signaling. Rats received SCMC for 7 days and a single CP dose on day 5. CP provoked severe cardiac injury, evidenced by increased CK-MB, LDH, and troponin-I, alongside histopathological alterations, including vascular congestion, cytoplasmic vacuolation, hypertrophy, and nuclear pyknosis. SCMC significantly alleviated cardiac biomarkers and mitigated tissue damage in CP-treated rats. CP increased MDA, decreased antioxidants, increased cardiac NF-κB, IL-1β, and gasdermin D, upregulated NLRP3, ASC1, and caspase-1, and diminished Nrf2 and HO-1. SCMC reduced MDA, enhanced antioxidant defenses, and downregulated NF-κB, NLRP3, ASC, caspase-1, gasdermin D, and IL-1β in CP-administered rats. In addition, SCMC enhanced the expression of Nrf2 and activity of HO-1 in the heart of CP-administered rats. In conclusion, these findings demonstrate that SCMC mitigates CP-induced cardiotoxicity by targeting oxidative injury and inflammatory signaling. Its cardioprotective mechanism includes mitigation of oxidative stress and NF-κB/NLRP3 inflammasome axis, and upregulation of Nrf2/HO-1 pathway. Given its established clinical safety, SCMC may represent a translatable adjunctive therapy to protect against CP-induced cardiotoxicity. However, further studies and clinical trials are warranted to confirm these findings.
2024-12-19 | A case of adult-onset X-linked lymphoproliferative disease mimicking pulmonary infection.
X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency with susceptibility and vulnerability to Epstein-Barr virus (EBV) infection. Most patients were diagnosed in early childhood and do not survive into adulthood. Here we reported an adult-onset XLP patient presenting with fever, dyspnea, and pulmonary nodules, mimicking respiratory infection at disease onset. Diagnosis was made based on whole-exon sequencing and pedigree analysis. Chest CT showed bilateral nodular lesions partially responsive to steroid therapy. The symptoms were managed with high-dose steroid, together with broad-spectrum anti-infective treatment for mixed secondary opportunistic infections. Pathology studies revealed non-Langerhans histiocytosis and T cell infiltration in lungs. Our case highlights the importance of genetic sequencing in managing young patients with unexplained infection and potential immuno-deficiency. We also added to the understanding of XLP by carrying detailed investigation into the pulmonary lesions.
2024-05-01 | X-Linked Lymphoproliferative Disease Type 2 With Activation of Hemophagocytic Lymphohistiocytosis Secondary to Epstein-Barr Virus Infection
Hemophagocytic lymphohistiocytosis (HLH) is a rare yet potentially life-threatening syndrome. It is best described as uncontrolled immune system activation leading to hemophagocytosis. Our case report aims to present a practical approach, discuss the challenges in the diagnosis and management of HLH, and to shed light on the X-linked lymphoproliferative disease type 2 (XLP-2) gene, STXBP2 gene (as a carrier), and Epstein-Barr virus (EBV) infection in relation to HLH. This is a 2-year-8-month-old Saudi boy, who presented to the emergency department with fever for more than 7 days, not associated with any other major complaints. During the first couple of days of admission, primary results showed hyperferritinemia, low fibrinogen, anemia, high inflammatory markers, high D-dimer, and increasing liver enzymes and triglycerides. The patient fulfilled the diagnostic criteria of HLH on the third day of admission. Further investigations revealed a genetic mutation in XLP-2 gene, STXBP2 gene (as a carrier) and EBV infection causing HLH. HLH-94 protocol was used for management. The patient had an excellent clinical outcome, unexpectedly, by only using dexamethasone, with complete remission and no recurrence up to date. HLH is not frequently encountered in daily practice. However, it can be fatal. This case report describes a unique case of XLP-2, STXBP2 carrier with extreme EBV infection and activation of HLH, who was successfully brought into remission by partial application of HLH-94 protocol and careful clinical and laboratory monitoring. The diagnosis and management of HLH can be challenging. However, a reasonable clinical judgment can improve the outcomes. Int J Clin Pediatr. 2024;13(1):26-33 doi: https://doi.org/10.14740/ijcp525
2023-12-16 | The inhibition of IRE1alpha/XBP1 axis prevents EBV-driven lymphomagenesis in NSG mice.
The novelty of this study lies in the fact that it shows that IRE1 alpha endoribonuclease inhibition by 4μ8C was able to counteract Epstein-Barr virus-driven lymphomagenesis in NOD SCID gamma mice and prevent B-cell immortalization in vitro, unveiling that this drug may be a promising therapeutic approach to reduce the risk of post-transplant lymphoproliferative disorders (PTLD) onset in immune-deficient patients. This hypothesis is further supported by the fact that 4μ8C impaired the survival of PTLD-like cells derived from mice, meaning that it could be helpful also in the case in which there is the possibility that these malignancies have begun to arise.
2023-07-07 | XIAP promotes the expansion and limits the contraction of CD8 T cell response through cell extrinsic and intrinsic mechanisms respectively.
XIAP is an endogenous inhibitor of cell death and inactivating mutations of XIAP are responsible for X-linked lymphoproliferative disease (XLP-2) and primary immunodeficiency, but the mechanism(s) behind these contradictory outcomes have been unclear. We report that during infection of macrophages and dendritic cells with various intracellular bacteria, XIAP restricts cell death and secretion of IL-1β but promotes increased activation of NFκB and JNK which results in elevated secretion of IL-6 and IL-10. Poor secretion of IL-6 by Xiap-deficient antigen presenting cells leads to poor expansion of recently activated CD8 T cells during the priming phase of the response. On the other hand, Xiap-deficient CD8 T cells displayed increased proliferation and effector function during the priming phase but underwent enhanced contraction subsequently. Xiap-deficient CD8 T cells underwent skewed differentiation towards short lived effectors which resulted in poor generation of memory. Consequently Xiap-deficient CD8 T cells failed to provide effective control of bacterial infection during re-challenge. These results reveal the temporal impact of XIAP in promoting the fitness of activated CD8 T cells through cell extrinsic and intrinsic mechanisms and provide a mechanistic explanation of the phenotype observed in XLP-2 patients.
antibodies
2026-08-20 | Epstein Barr Virus–Driven Hodgkin Lymphoma in a Patient with X-linked Lymphoproliferative Disease Type 1 and XYY Karyotype: Rare Association
Introduction X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency caused by pathogenic variants in the SH2D1A gene, characterized by a dysregulated immune response to Epstein–Barr virus (EBV), hypogammaglobulinemia, a markedly increased risk of hemophagocytic lymphohistiocytosis (HLH) and EBV-driven lymphoproliferation, while Hodgkin lymphoma (HL) represents an exceptionally rare complication. Case Presentation We report a male patient diagnosed with XLP1 at the age of six following his first episode of HLH, with confirmation of a pathogenic SH2D1A variant. Cytogenetic analysis revealed a 47, XYY karyotype. The patient remained clinically stable until the age of 28, when he experienced a new episode of EBV reactivation-associated HLH. Treatment with dexamethasone and immunomodulatory doses of intravenous immunoglobulin (IVIG) resulted in prompt clinical improvement, and a long-term IVIG replacement was initiated due to hypogammaglobulinemia. Four months later, the patient presented with severe abdominal pain, fever, pancytopenia, splenomegaly, hyperferritinemia, and markedly elevated soluble IL-2 receptor levels (9,840 IU/mL), consistent with a third episode of EBV-associated HLH (viral load 207,000 viral copies/mL). Treatment was initiated according to the HLH-2014 protocol, including dexamethasone, immunomodulatory IVIG, and rituximab. Despite transient improvement, clinical and laboratory deterioration occurred, prompting escalation with high-dose methylprednisolone pulses, leading to significant clinical improvement. Interestingly, bone marrow biopsy performed before treatment revealed infiltration consistent with HL. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) demonstrated active disease in the spleen and bone marrow, establishing a stage IVA diagnosis. Chemotherapy with the ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) protocol was initiated. After two cycles, interim FDG-PET/CT showed complete metabolic remission (Deauville score 1/2), and treatment continued with four cycles of AVD, according to European Society for Medical Oncology (ESMO) guidelines. Key Messages for Clinical Practice This case illustrates that XLP1 patients remain at lifelong risk for EBV-driven HLH and rare lymphomas, and emphasizes that early recognition, vigilant monitoring, and prompt targeted therapy, including rituximab and tailored chemotherapy, can achieve complete remission, even in this high-risk population.
2025-06-19 | The PD-1/PD-L1 pathway and Epstein-Barr virus.
Epstein-Barr virus (EBV) is a gamma-herpesvirus with double-stranded DNA. Primary EBV infection leads to infectious mononucleosis (IM) in 20-50% of children and young adults. EBV establishes latent infection in B lymphocytes and can infect T lymphocytes and NK cells, potentially causing lymphoproliferative disorders (LPD) and malignancies. While the PD-1/PD-L1 pathway's role in chronic viral infections is well-established, its specific functions in EBV infection remain poorly understood. Growing evidence suggests this pathway facilitates EBV immune evasion, yet the effect of PD-1 upregulation on Epstein-Barr virus-specific CD8 + T cell function during acute IM is unclear. Furthermore, the role of PD-1/PD-L1 pathway in cytotoxic T cells and immune regulation during EBV infection is still controversial. This review systematically analyzes current knowledge on PD-1/PD-L1 signaling in EBV infection, focusing on three key aspects: (1) its dual role in maintaining immune homeostasis during acute infection while potentially facilitating viral persistence, (2) its emerging potential as a diagnostic biomarker for disease progression and prognosis, particularly during acute infectious mononucleosis, and (3) the therapeutic implications of pathway modulation. We critically evaluate recent advances that position PD-1/PD-L1 at the intersection of virology and tumor immunology, while highlighting important unanswered questions that require further investigation to optimize EBV-specific immunotherapies.
2025-04-25 | The Difference in Presentation of Cases of X-Linked Lymphoproliferative Disease Type 1 in a Family of Three Boys
Introduction X-linked lymphoproliferative disease type 1 (XLP-1) is a rare syndrome caused by an inactivating mutation in SH2D1A, which encodes for SLAM-Associated protein (SAP) on T and natural killer (NK) cells. The three classic manifestations of XLP-1 include Epstein–Barr virus (EBV)–induced hemophagocytic lymphohistiocytosis (HLH), B cell lymphoma, and dys-gammaglobulinemia. Genotype–phenotype correlation between patients with SH2D1A mutations is unknown. It is unclear how SAP protein levels are related to disease development. We describe a case of a family of 3 boys who had a pathogenic mutation in SH2D1A with different clinical phenotypes. Case Brother 1 is a 2-year-old fully vaccinated male who initially presented to our immunology clinic for evaluation of recurrent ear infections. He was found to have low IgG (179 mg/dL), low IgM (<10 mg/dL), and failure to respond to multiple pediatric vaccines. Genetic testing showed a variant of unknown significance (VUS) in SH2D1A (hemizygous, c.95G>A p.Arg32Lys). Flow cytometry for SAP showed decreased expression of SAP in CD4 (28%), CD8 (23%), and NK cells (46%), suggesting a pathogenic VUS. Brother 2 is a 4-year-old boy who was initially referred to the hospital for hypoxia in the setting of a multifocal pneumonia of unclear etiology. He quickly decompensated and required ECMO for respiratory support. Genetic testing showed the same mutation in SH2D1A as brother 1. Flow cytometry showed decreased expression of SAP in CD4 (8%), CD8 (4%), and NK cells (47%). He met 5 of 8 criteria for HLH. He passed away despite treatment with gamifant and anakinra. Brother 3 is an 8-year-old fully vaccinated boy who also has the same pathogenic mutation in SH2D1A as both brothers. His immune workup was essentially normal except for a non-protective titer to tetanus toxoid. Flow cytometry for SAP showed slightly higher but low expression in CD4 (68%), CD8 (40%), and NK cells (86%). Conclusion Our case highlights the clinical variability of XLP-1 presentation in a family with the same pathogenic variant in SH2D1A. We conclude that the SH2D1A VUS is pathogenic and that SAP levels can correlate with severity of disease.
2024-04-19 | Case report: EBV-related eye orbits and sinuses lymphohistiocytic infiltration responsive to rituximab in a patient with X lymphoproliferative syndrome type 1.
X lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity due to mutations of SH2D1A, encoding for slam-associated protein (SAP). The clinical phenotype includes severe mononucleosis, hemophagocytic lymphohistiocytosis (HLH), and B-cell lymphomas. We report the case of a child affected with XLP1 who presented with an incomplete HLH, triggered by Epstein-Barr virus (EBV) and treated with rituximab, involving orbits and paranasal sinuses. The lesion was indistinguishable from lymphoma, complicating diagnosis and treatment. In addition, considering the high incidence of lymphoma in patients with XLP1, histology helped define its nature, driving therapeutic choices. We described an unusual presentation of incomplete HLH in a patient affected with XLP1: an EBV-driven infiltration of the orbits and paranasal sinuses. This led us to a challenging differential diagnosis of lymphoma-associated hemophagocytic syndrome, which can be frequently observed in patients with XLP1. Considering the extremely poor prognosis of this clinical finding, we sought for a prompt diagnosis and managed to obtain it and to immediately establish the right treatment on the basis of the pathological finding.
2023-09-25 | X-linked lymphoproliferative syndrome associated with Epstein-Barr virus encephalitis and lymphoproliferative disorder.
When treating patients with EBV encephalitis, the possibility of XLP should be considered. Once the diagnosis of XLP is made, aggressive treatment such as rituximab, and other immunosuppressive agents are desired for rapid transition to HSCT.
cell therapies
2026-08-22 | Genetic and autoimmune predispositions to fulminant viral hepatitis in children.
Fulminant viral hepatitis (FVH) in children is a rare but often fatal form of acute liver failure occurring in the absence of preexisting liver disease. Its exceptional incidence during otherwise common viral infections, including hepatitis A virus (HAV), hepatitis B virus (HBV), and herpes simplex virus (HSV), supports a decisive role for host susceptibility. Recent advances in human immunogenetics delineate two major, mechanistically distinct pathways to pediatric FVH. The first reflects failure of immune regulation, culminating in excessive IFN-γ-driven inflammation and immune-mediated hepatocellular necrosis. Autosomal recessive IL-18BP and IL-10RB deficiencies exemplify this mechanism, in which disruption of key regulatory checkpoints permits uncontrolled activation of cytotoxic lymphocytes and macrophage-dependent immunopathology, particularly in the context of HAV infection. The second pathway involves impaired intrinsic antiviral defense, most prominently through neutralizing autoantibodies against type I interferons, which phenocopy genetic defects of IFN-I signaling and are strongly associated with HSV-triggered FVH; in this setting, inadequate early antiviral control enables unchecked hepatic replication with extensive cytopathic damage. Finally, syndromic hyperinflammatory disorders, including familial hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease, broaden the spectrum of immune predisposition in which fulminant hepatitis may arise. Together, these discoveries redefine pediatric FVH as an immunopathological syndrome and provide a framework for targeted genetic and serologic diagnosis and for mechanism-based interventions aimed at improving survival.
2025-10-22 | The neurologic face of X-linked lymphoproliferative syndrome type 1: a systematic review.
BACKGROUND: X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity with high mortality rates. Neurological manifestations may be the presenting features and are often fatal; however, their characterization is insufficient, hindering optimal clinical management. The aim of this study is to systematically review the neurological characteristics, outcomes, and survival in XLP1 patients and identify parameters associated with improved prognosis. A PRISMA-guided analysis of PubMed, Web of Science, Scopus, and Embase (up to March 2025) identified studies documenting neurological involvement in genetically verified XLP1 patients. We extracted data on clinical features, neuroimaging findings, therapeutic interventions, and survival. RESULTS: We identified 42 genetically verified XLP1 patients with neurological involvement. Central nervous system (CNS) involvement comprised hemophagocytic lymphohistiocytosis (HLH) in 38.1%, vasculitis in 28.6%, and lymphoma in 19% of them. The development of brain vasculitis several months after Burkitt’s lymphoma was a specific presentation. The median age of neurological onset was 5 years. The predominant presenting symptoms were seizures (47.6%), altered consciousness (35.7%), and headaches (21.4%). Neuroimaging frequently revealed abnormalities in the temporal lobe and basal ganglia, often with hemorrhage and edema. Epstein-Barr virus (EBV) was identified in 54.8% of cases, sometimes limited to brain tissue. CSF analysis frequently showed elevated protein and pleocytosis. SH2D1A mutations were diverse, with Arg55 and Trp64 identified as recurrent hot spots. The overall mortality reached 52.4%, with most deaths occurring within five years of neurological onset. Conventional immunosuppressive and cytotoxic treatments were largely ineffective in changing the disease course. In exploratory analysis, hematopoietic stem cell transplantation (HSCT) did not significantly improve survival in the primary dataset, although sensitivity analysis suggested a possible benefit. CONCLUSIONS: Neurological involvement in XLP1 exhibits clinical heterogeneity and carries a high mortality rate. Early recognition and timely HSCT may improve survival, demonstrating the importance of vigilant neurological monitoring in affected individuals.
2025-05-22 | Targeting intracellular LMP2 with costimulatory signal-armed antibody-like TCR T cells.
Expanding the repertoire of CAR therapies to include intracellular antigens holds promise for treating a broad spectrum of malignancies. TCR-like T cells, capable of recognizing intracellular antigen-derived peptides in complex with HLA molecules (pHLA), represent a promising strategy in the field of engineered cellular therapy. This study introduced antibody-like TCR (abTCR) T cells that specifically targeted HLA-A*02:01-restricted LMP2426 peptides, a typical Epstein-Barr virus (EBV) latency II protein, for the treatment of EBV-associated lymphoproliferative diseases (EBV-LPDs). Compared with classic CAR T cells targeting the same epitope, abTCR T cells demonstrated superior efficiency, including increased CD107A expression, enhanced cytotoxicity, and elevated IFN-γ secretion, even when engaging with target cells that naturally present antigens. Moreover, a costimulatory signal-armed abTCR (Co-abTCR), which integrated a costimulatory structure with the abTCR, further enhanced the proliferation and in vivo tumoricidal efficacy of transfected T cells. Collectively, our study developed a potentially novel TCR-like T cell therapy that targets HLA-A*02/LMP2426 for the treatment of EBV-LPDs, providing a potential therapeutic solution for targeting of intracellular antigens in cancer immunotherapy.
2022-04-18 | Preemptive hematopoietic cell transplantation for asymptomatic patients with X-linked lymphoproliferative syndrome type 1.
Few reports have examined whether prophylactic allogeneic hematopoietic cell transplantation (HCT) for X-linked lymphoproliferative syndrome type 1 (XLP1) improves the prognosis. We compared the prognosis of symptomatic probands and affected siblings in the same family. Twenty-two cases (10 probands and 12 affected siblings) in Japan, the United Kingdom, and the United States were analyzed. The overall survival (OS) rate at 5 years after diagnosis was 70.0% in probands and 91.7% in affected siblings (p = 0.0789). The prognosis of patients who developed symptoms of XLP1 before HCT and those who did not was also compared. The 5-year probability of OS from the time of diagnosis in asymptomatic patients (100%) was significantly better than that in symptomatic patients (66.7%). These results suggested that early HCT as soon as the diagnosis is made improves the prognosis in asymptomatic XLP1 patients.
2022-01-05 | Two Clonally Distinct B-Cell Lymphomas Reveal the Diagnosis of XLP1 in a Male Child and His Asymptomatic Male Relatives: Case Report and Review of the Literature.
X-linked lymphoproliferative disease type 1 (XLP1) is a primary immunodeficiency disorder caused by pathogenic variants in the SH2D1A gene (SH2 domain containing protein 1A). Patients with XLP1 may present acutely with fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, and/or B-cell non-Hodgkin lymphoma (B-NHL). We report a boy who developed 2 clonally distinct B-NHL 4 years apart and was found to have previously unrecognized XLP1. The report highlights the importance of clonal analysis and XLP1 testing in males with presumed late recurrences of B-NHL, and the role of allogeneic stem cell transplant (allo-SCT) in XLP1 patients and their affected male relatives.
other
2026-01-08 | Polyclonal evolution of lymphoproliferative disorders in XLP1
X-linked lymphoproliferative syndrome type 1 (XLP1) is an inborn error of immunity caused by pathogenic variants in SH2D1A and is frequently complicated by Epstein-Barr virus (EBV)–associated lymphoproliferative disorders (LPDs). However, cases of LPD without EBV infection have been reported and remain poorly understood. We investigated tumorigenesis mechanisms through transcriptomic profiling and somatic variant analysis in tumor samples from six patients with XLP1. Pathogenic variants were identified in two: one developed two distinct LPDs harboring CARD11/GNA13 and MECOM variants, while the other carried IRF4, P2RY8, KRAS, and CCND3 variants. Transcriptome analysis of three tumors, compared with diffuse large B cell lymphoma from patients without an underlying immune defect, revealed a distinct expression profile. Gene Ontology analysis showed upregulation of adaptive immune response genes, including various IgH and TCR genes, suggesting polyclonal lymphocyte proliferation. Overall, LPD associated with XLP1 may originate from polyclonal lymphocyte expansion, either in the presence or absence of EBV infection, and subsequently progress to malignancy through somatic variants.
2025-06-27 | X-linked lymphoproliferative disease type 1: a clinical and genetic update.
X-linked lymphoproliferative disease (XLP), also known as Duncan's disease, is a primary immunodeficiency disorder linked to the X chromosome. In 1998, SH2D1A, which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), was identified as the first pathogenic gene associated with XLP. To date, more than 100 mutation sites in this gene have been documented. The disease is associated with infection with Epstein-Barr virus (EBV) and characterized by hemophagocytic lymphohistiocytosis (HLH), hypogammaglobulinemia, and lymphomas. Pathogenesis is intricately associated with cell type-specific SAP-SLAM signaling pathways. Particularly, the immune cell defects involve impaired T cell-B cell interactions, reduced cytotoxicity of Natural Killer (NK) cells, and abnormal development of Natural Killer T (NKT) cells. These factors collectively increase susceptibility to EBV and drive clinical manifestations in XLP type 1 (XLP1) patients. Although establishing a definitive correlation between specific genotypes and clinical phenotypes remains challenging, emerging evidence suggests a potential association. This underscores the critical need for further large-scale studies to elucidate this relationship. Given the current understanding of the pathophysiological mechanisms associated with XLP1, specific treatments to normalize SAP expression and restore immune tolerance in XLP1 patients play an important role. In addition to the necessity for long-term studies to verify the efficacy and safety of hematopoietic stem cell transplantation (HSCT), gene therapies currently under development, along with other emerging treatments, exhibit substantial promise for future clinical applications.
2023-02-03 | Lentiviral Gene Transfer Corrects Immune Abnormalities in XIAP Deficiency.
X-linked inhibitor of apoptosis protein (XIAP) deficiency is a severe immunodeficiency with clinical features including hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD) due to defective NOD2 responses. Management includes immunomodulatory therapies and hematopoietic stem cell transplant (HSCT). However, this cohort is particularly susceptible to the chemotherapeutic regimens and acutely affected by graft-vs-host disease (GvHD), driving poor long-term survival in transplanted patients. Autologous HSC gene therapy could offer an alternative treatment option and would abrogate the risks of alloreactivity. Hematopoietic progenitor (Lin-ve) cells from XIAPy/- mice were transduced with a lentiviral vector encoding human XIAP cDNA before transplantation into irradiated XIAP y/- recipients. After 12 weeks animals were challenged with the dectin-1 ligand curdlan and recovery of innate immune function was evaluated though analysis of inflammatory cytokines, body weight, and splenomegaly. XIAP patient-derived CD14+ monocytes were transduced with the same vector and functional recovery was demonstrated using in vitro L18-MDP/NOD2 assays. In treated XIAPy/- mice, ~40% engraftment of gene-corrected Lin-ve cells led to significant recovery of weight loss, splenomegaly, and inflammatory cytokine responses to curdlan, comparable to wild-type mice. Serum IL-6, IL-10, MCP-1, and TNF were significantly reduced 2-h post-curdlan administration in non-corrected XIAPy/- mice compared to wild-type and gene-corrected animals. Appropriate reduction of inflammatory responses was observed in gene-corrected mice, whereas non-corrected mice developed an inflammatory profile 9 days post-curdlan challenge. In gene-corrected patient CD14+ monocytes, TNF responses were restored following NOD2 activation with L18-MDP. Gene correction of HSCs recovers XIAP-dependent immune defects and could offer a treatment option for patients with XIAP deficiency.
2021-06-22 | T cell gene therapy to treat immunodeficiency.
The application of therapeutic T cells for a number of conditions has been developed over the past few decades with notable successes including donor lymphocyte infusions, virus-specific T cells and more recently CAR-T cell therapy. Primary immunodeficiencies are monogenetic disorders leading to abnormal development or function of the immune system. Haematopoietic stem cell transplantation and, in specific candidate diseases, haematopoietic stem cell gene therapy has been the only definitive treatment option so far. However, autologous gene-modified T cell therapy may offer a potential cure in conditions primarily affecting the lymphoid compartment. In this review we will highlight several T cell gene addition or gene-editing approaches in different target diseases with a focus on what we have learnt from clinical experience and promising preclinical studies in primary immunodeficiencies. Functional T cells are required not only for normal immune responses to infection (affected in CD40 ligand deficiency), but also for immune regulation [disrupted in IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-Linked) due to dysfunctional FOXP3 and CTLA4 deficiency] or cytotoxicity [defective in X-lymphoproliferative disease and familial haemophagocytic lymphohistiocytosis (HLH) syndromes]. In all these candidate diseases, restoration of T cell function by gene therapy could be of great value.
2019-08-02 | Transfer of gene-corrected T cells corrects humoral and cytotoxic defects in patients with X-linked lymphoproliferative disease.
X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell-dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia. Curative treatment is limited to hematopoietic stem cell transplantation, with outcomes reliant on a good donor match. Because most symptoms arise from defective T-cell function, we investigated whether transfer of SAP gene-corrected T cells could reconstitute known effector cell defects. CD3+ lymphocytes from Sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sublethally irradiated Sap-deficient recipients. After immunization with the T-dependent antigen 4-hydroxy-3-nitrophenylacetly chicken gammaglobulin (NP-CGG), recovery of humoral function was evaluated through germinal center formation and antigen-specific responses. To efficiently transduce CD3+ cells from patients, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated by using in vitro cytotoxicity and T follicular helper cell function assays alongside tumor clearance in an in vivo lymphoblastoid cell line lymphoma xenograft model. In Sap-deficient mice 20% to 40% engraftment of gene-modified T cells led to significant recovery of germinal center formation and NP-specific antibody responses. Gene-corrected T cells from patients demonstrated improved cytotoxicity and T follicular helper cell function in vitro. Adoptive transfer of gene-corrected cytotoxic T lymphocytes from patients reduced tumor burden to a level comparable with that seen in healthy donor cytotoxic T lymphocytes in an in vivo lymphoma model. These data demonstrate that autologous T-cell gene therapy corrects SAP-dependent defects and might offer an alternative therapeutic option for patients with X-linked lymphoproliferative disease 1.
proteins
2026-01-16 | Acquired nonpermissive BM microenvironment impairs HSC proliferation and maintenance, and B-cell development after HSCT.
Defects in B-cell reconstitution upon hematopoietic stem cell (HSC) transplant (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective, and complete B-cell deficiency in the context of full donor chimerism in a patient with X-linked lymphoproliferative disease, and aimed to identify the contribution of the BM microenvironment in disrupted B-cell reconstitution after HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the BM of the index patient, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy HSCs, which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients' MSCs, and a progressive loss of CXCL12 expression. Indeed, survival of the patients' HSCs improved upon supplementing the in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent nonpermissive state for normal B-cell development.
2025-07-08 | X-linked lymphoproliferative syndrome type 1 presenting as DRESS-HLH overlap syndrome.
A preadolescent male, born to 3rd-degree consanguineous parents, presented with persistent fever, cough and dyspnoea. He had non-resolving suppurative otitis media and two episodes of pneumonia in the past 2 years. During admission, clinical and radiological evaluations revealed bilateral lung consolidation with synpneumonic effusion. Examination also revealed the absence of bilateral tonsils. Blood and pleural fluid cultures were sterile. The child developed a drug reaction with eosinophilia and systemic symptoms (DRESS) associated with haemophagocytic-lymphohistiocytic syndrome (HLH) during the hospital stay. Given his history of recurrent infections and absent tonsils, primary immunodeficiency disorder was suspected. Immunological work-up showed reduced levels of IgG and IgM in serum. Exome sequencing identified a mutation in the SH2D1A gene confirming a diagnosis of X-linked lymphoproliferative syndrome (Duncan syndrome). The child was started on regular intravenous immunoglobulin therapy, along with bacterial and fungal prophylaxis. His parents were counselled regarding the prognosis and necessity of haematopoietic stem cell transplantation as the definitive treatment.
2024-09-23 | Lentiviral vectors for precise expression to treat X-linked lymphoproliferative disease.
X-linked lymphoproliferative disease (XLP1) results from SH2D1A gene mutations affecting the SLAM-associated protein (SAP). A regulated lentiviral vector (LV), XLP-SMART LV, designed to express SAP at therapeutic levels in T, NK, and NKT cells, is crucial for effective gene therapy. We experimentally identified 34 genomic regulatory elements of the SH2D1A gene and designed XLP-SMART LVs to emulate the lineage and stage-specific control of SAP. We screened them for their on-target enhancer activity in T, NK, and NKT cells and their off-target enhancer activity in B cell and myeloid populations. In combination, three enhancer elements increased SAP promoter expression up to 4-fold in on-target populations in vitro. NSG-Tg(Hu-IL15) xenograft studies with XLP-SMART LVs demonstrated up to 7-fold greater expression in on-target cells over a control EFS-LV, with no off-target expression. The XLP-SMART LVs exhibited stage-specific T and NK cell expression in peripheral blood, bone marrow, spleen, and thymic tissues (mimicking expression patterns of SAP). Transduction of XLP1 patient CD8+ T cells or BM CD34+ cells with XLP-SMART LVs restored restimulation-induced cell death and NK cytotoxicity to wild-type levels, respectively. These data demonstrate that it is feasible to create a lineage and stage-specific LV to restore the XLP1 phenotype by gene therapy.
2021-12-23 | Epstein-Barr virus (EBV) hyperimmune globulin isolated from donors with high gp350 antibody titers protect humanized mice from challenge with EBV.
Primary infection with Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease and severe disease in patients with X-linked lymphoproliferative disease; no therapies are approved to prevent EBV infection in these patients. Hyperimmune globulin has been used to prevent some virus infections in immunocompromised persons. Here, we identified plasma donors with high titers of EBV gp350 and EBV B cell neutralizing antibodies. Pooled IgG isolated from these donors was compared to intravenous immunoglobulin (IVIG) for its ability to reduce viral load in the blood in humanized mice challenged with EBV. Mice that received EBV hyperimmune globulin had significantly reduced EBV DNA copy numbers compared to animals that received saline control; however, while animals that received EBV hyperimmune globulin had lower EBV DNA copies than those that received IVIG, the difference was not significant. Thus, while EBV hyperimmune globulin reduced viral load compared to IVIG, the effect was modest.
2019-05-13 | FOXP3 renders activated human regulatory T cells resistant to restimulation-induced cell death by suppressing SAP expression.
Restimulation-induced cell death (RICD) is an apoptotic program that regulates effector T cell expansion, triggered by repeated stimulation through the T cell receptor (TCR) in the presence of interleukin-2 (IL-2). Although CD4+ regulatory T cells (Tregs) consume IL-2 and experience frequent TCR stimulation, they are highly resistant to RICD. Resistance in Tregs is dependent on the forkhead box P3 (FOXP3) transcription factor, although the mechanism remains unclear. T cells from patients with X-linked lymphoproliferative disease (XLP-1), that lack the adaptor molecule SLAM-associated protein (SAP), are also resistant to RICD. Here we demonstrate that normal Tregs express very low levels of SAP compared to conventional T cells. FOXP3 reduces SAP expression by directly binding to and repressing the SH2D1A (SAP) promoter. Indeed, ectopic SAP expression restores RICD sensitivity in human FOXP3+ Tregs. Our findings illuminate the mechanism behind FOXP3-mediated RICD resistance in Tregs, providing new insight into their long-term persistence.
small molecules
2025-08-18 | Attenuation of NF-κB/NLRP3 inflammasome axis and oxidative stress, and upregulation of Nrf2/HO-1 signaling mediate the protective effect of S-carboxymethylcysteine against cyclophosphamide-induced cardiotoxicity.
Cyclophosphamide (CP) is a potent chemotherapeutic and immunosuppressant agent used in the management of lymphoproliferative disorders and solid tumors. However, it induces cardiotoxicity and other severe adverse effects, thereby limiting its clinical application, highlighting the need for safe and effective cardioprotective agents. This study investigates the cardioprotective potential of carbocysteine (S-carboxymethylcysteine (SCMC)), a mucolytic agent with emerging pleiotropic properties, against CP-induced toxicity. The study explores the effect of SCMC on oxidative stress, NF-κB/NLRP3 inflammasome axis and Nrf2/HO-1 signaling. Rats received SCMC for 7 days and a single CP dose on day 5. CP provoked severe cardiac injury, evidenced by increased CK-MB, LDH, and troponin-I, alongside histopathological alterations, including vascular congestion, cytoplasmic vacuolation, hypertrophy, and nuclear pyknosis. SCMC significantly alleviated cardiac biomarkers and mitigated tissue damage in CP-treated rats. CP increased MDA, decreased antioxidants, increased cardiac NF-κB, IL-1β, and gasdermin D, upregulated NLRP3, ASC1, and caspase-1, and diminished Nrf2 and HO-1. SCMC reduced MDA, enhanced antioxidant defenses, and downregulated NF-κB, NLRP3, ASC, caspase-1, gasdermin D, and IL-1β in CP-administered rats. In addition, SCMC enhanced the expression of Nrf2 and activity of HO-1 in the heart of CP-administered rats. In conclusion, these findings demonstrate that SCMC mitigates CP-induced cardiotoxicity by targeting oxidative injury and inflammatory signaling. Its cardioprotective mechanism includes mitigation of oxidative stress and NF-κB/NLRP3 inflammasome axis, and upregulation of Nrf2/HO-1 pathway. Given its established clinical safety, SCMC may represent a translatable adjunctive therapy to protect against CP-induced cardiotoxicity. However, further studies and clinical trials are warranted to confirm these findings.
2024-12-19 | A case of adult-onset X-linked lymphoproliferative disease mimicking pulmonary infection.
X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency with susceptibility and vulnerability to Epstein-Barr virus (EBV) infection. Most patients were diagnosed in early childhood and do not survive into adulthood. Here we reported an adult-onset XLP patient presenting with fever, dyspnea, and pulmonary nodules, mimicking respiratory infection at disease onset. Diagnosis was made based on whole-exon sequencing and pedigree analysis. Chest CT showed bilateral nodular lesions partially responsive to steroid therapy. The symptoms were managed with high-dose steroid, together with broad-spectrum anti-infective treatment for mixed secondary opportunistic infections. Pathology studies revealed non-Langerhans histiocytosis and T cell infiltration in lungs. Our case highlights the importance of genetic sequencing in managing young patients with unexplained infection and potential immuno-deficiency. We also added to the understanding of XLP by carrying detailed investigation into the pulmonary lesions.
2024-05-01 | X-Linked Lymphoproliferative Disease Type 2 With Activation of Hemophagocytic Lymphohistiocytosis Secondary to Epstein-Barr Virus Infection
Hemophagocytic lymphohistiocytosis (HLH) is a rare yet potentially life-threatening syndrome. It is best described as uncontrolled immune system activation leading to hemophagocytosis. Our case report aims to present a practical approach, discuss the challenges in the diagnosis and management of HLH, and to shed light on the X-linked lymphoproliferative disease type 2 (XLP-2) gene, STXBP2 gene (as a carrier), and Epstein-Barr virus (EBV) infection in relation to HLH. This is a 2-year-8-month-old Saudi boy, who presented to the emergency department with fever for more than 7 days, not associated with any other major complaints. During the first couple of days of admission, primary results showed hyperferritinemia, low fibrinogen, anemia, high inflammatory markers, high D-dimer, and increasing liver enzymes and triglycerides. The patient fulfilled the diagnostic criteria of HLH on the third day of admission. Further investigations revealed a genetic mutation in XLP-2 gene, STXBP2 gene (as a carrier) and EBV infection causing HLH. HLH-94 protocol was used for management. The patient had an excellent clinical outcome, unexpectedly, by only using dexamethasone, with complete remission and no recurrence up to date. HLH is not frequently encountered in daily practice. However, it can be fatal. This case report describes a unique case of XLP-2, STXBP2 carrier with extreme EBV infection and activation of HLH, who was successfully brought into remission by partial application of HLH-94 protocol and careful clinical and laboratory monitoring. The diagnosis and management of HLH can be challenging. However, a reasonable clinical judgment can improve the outcomes. Int J Clin Pediatr. 2024;13(1):26-33 doi: https://doi.org/10.14740/ijcp525
2023-12-16 | The inhibition of IRE1alpha/XBP1 axis prevents EBV-driven lymphomagenesis in NSG mice.
The novelty of this study lies in the fact that it shows that IRE1 alpha endoribonuclease inhibition by 4μ8C was able to counteract Epstein-Barr virus-driven lymphomagenesis in NOD SCID gamma mice and prevent B-cell immortalization in vitro, unveiling that this drug may be a promising therapeutic approach to reduce the risk of post-transplant lymphoproliferative disorders (PTLD) onset in immune-deficient patients. This hypothesis is further supported by the fact that 4μ8C impaired the survival of PTLD-like cells derived from mice, meaning that it could be helpful also in the case in which there is the possibility that these malignancies have begun to arise.
2023-07-07 | XIAP promotes the expansion and limits the contraction of CD8 T cell response through cell extrinsic and intrinsic mechanisms respectively.
XIAP is an endogenous inhibitor of cell death and inactivating mutations of XIAP are responsible for X-linked lymphoproliferative disease (XLP-2) and primary immunodeficiency, but the mechanism(s) behind these contradictory outcomes have been unclear. We report that during infection of macrophages and dendritic cells with various intracellular bacteria, XIAP restricts cell death and secretion of IL-1β but promotes increased activation of NFκB and JNK which results in elevated secretion of IL-6 and IL-10. Poor secretion of IL-6 by Xiap-deficient antigen presenting cells leads to poor expansion of recently activated CD8 T cells during the priming phase of the response. On the other hand, Xiap-deficient CD8 T cells displayed increased proliferation and effector function during the priming phase but underwent enhanced contraction subsequently. Xiap-deficient CD8 T cells underwent skewed differentiation towards short lived effectors which resulted in poor generation of memory. Consequently Xiap-deficient CD8 T cells failed to provide effective control of bacterial infection during re-challenge. These results reveal the temporal impact of XIAP in promoting the fitness of activated CD8 T cells through cell extrinsic and intrinsic mechanisms and provide a mechanistic explanation of the phenotype observed in XLP-2 patients.
antibodies
2026-08-20 | Epstein Barr Virus–Driven Hodgkin Lymphoma in a Patient with X-linked Lymphoproliferative Disease Type 1 and XYY Karyotype: Rare Association
Introduction X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency caused by pathogenic variants in the SH2D1A gene, characterized by a dysregulated immune response to Epstein–Barr virus (EBV), hypogammaglobulinemia, a markedly increased risk of hemophagocytic lymphohistiocytosis (HLH) and EBV-driven lymphoproliferation, while Hodgkin lymphoma (HL) represents an exceptionally rare complication. Case Presentation We report a male patient diagnosed with XLP1 at the age of six following his first episode of HLH, with confirmation of a pathogenic SH2D1A variant. Cytogenetic analysis revealed a 47, XYY karyotype. The patient remained clinically stable until the age of 28, when he experienced a new episode of EBV reactivation-associated HLH. Treatment with dexamethasone and immunomodulatory doses of intravenous immunoglobulin (IVIG) resulted in prompt clinical improvement, and a long-term IVIG replacement was initiated due to hypogammaglobulinemia. Four months later, the patient presented with severe abdominal pain, fever, pancytopenia, splenomegaly, hyperferritinemia, and markedly elevated soluble IL-2 receptor levels (9,840 IU/mL), consistent with a third episode of EBV-associated HLH (viral load 207,000 viral copies/mL). Treatment was initiated according to the HLH-2014 protocol, including dexamethasone, immunomodulatory IVIG, and rituximab. Despite transient improvement, clinical and laboratory deterioration occurred, prompting escalation with high-dose methylprednisolone pulses, leading to significant clinical improvement. Interestingly, bone marrow biopsy performed before treatment revealed infiltration consistent with HL. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) demonstrated active disease in the spleen and bone marrow, establishing a stage IVA diagnosis. Chemotherapy with the ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) protocol was initiated. After two cycles, interim FDG-PET/CT showed complete metabolic remission (Deauville score 1/2), and treatment continued with four cycles of AVD, according to European Society for Medical Oncology (ESMO) guidelines. Key Messages for Clinical Practice This case illustrates that XLP1 patients remain at lifelong risk for EBV-driven HLH and rare lymphomas, and emphasizes that early recognition, vigilant monitoring, and prompt targeted therapy, including rituximab and tailored chemotherapy, can achieve complete remission, even in this high-risk population.
2025-06-19 | The PD-1/PD-L1 pathway and Epstein-Barr virus.
Epstein-Barr virus (EBV) is a gamma-herpesvirus with double-stranded DNA. Primary EBV infection leads to infectious mononucleosis (IM) in 20-50% of children and young adults. EBV establishes latent infection in B lymphocytes and can infect T lymphocytes and NK cells, potentially causing lymphoproliferative disorders (LPD) and malignancies. While the PD-1/PD-L1 pathway's role in chronic viral infections is well-established, its specific functions in EBV infection remain poorly understood. Growing evidence suggests this pathway facilitates EBV immune evasion, yet the effect of PD-1 upregulation on Epstein-Barr virus-specific CD8 + T cell function during acute IM is unclear. Furthermore, the role of PD-1/PD-L1 pathway in cytotoxic T cells and immune regulation during EBV infection is still controversial. This review systematically analyzes current knowledge on PD-1/PD-L1 signaling in EBV infection, focusing on three key aspects: (1) its dual role in maintaining immune homeostasis during acute infection while potentially facilitating viral persistence, (2) its emerging potential as a diagnostic biomarker for disease progression and prognosis, particularly during acute infectious mononucleosis, and (3) the therapeutic implications of pathway modulation. We critically evaluate recent advances that position PD-1/PD-L1 at the intersection of virology and tumor immunology, while highlighting important unanswered questions that require further investigation to optimize EBV-specific immunotherapies.
2025-04-25 | The Difference in Presentation of Cases of X-Linked Lymphoproliferative Disease Type 1 in a Family of Three Boys
Introduction X-linked lymphoproliferative disease type 1 (XLP-1) is a rare syndrome caused by an inactivating mutation in SH2D1A, which encodes for SLAM-Associated protein (SAP) on T and natural killer (NK) cells. The three classic manifestations of XLP-1 include Epstein–Barr virus (EBV)–induced hemophagocytic lymphohistiocytosis (HLH), B cell lymphoma, and dys-gammaglobulinemia. Genotype–phenotype correlation between patients with SH2D1A mutations is unknown. It is unclear how SAP protein levels are related to disease development. We describe a case of a family of 3 boys who had a pathogenic mutation in SH2D1A with different clinical phenotypes. Case Brother 1 is a 2-year-old fully vaccinated male who initially presented to our immunology clinic for evaluation of recurrent ear infections. He was found to have low IgG (179 mg/dL), low IgM (<10 mg/dL), and failure to respond to multiple pediatric vaccines. Genetic testing showed a variant of unknown significance (VUS) in SH2D1A (hemizygous, c.95G>A p.Arg32Lys). Flow cytometry for SAP showed decreased expression of SAP in CD4 (28%), CD8 (23%), and NK cells (46%), suggesting a pathogenic VUS. Brother 2 is a 4-year-old boy who was initially referred to the hospital for hypoxia in the setting of a multifocal pneumonia of unclear etiology. He quickly decompensated and required ECMO for respiratory support. Genetic testing showed the same mutation in SH2D1A as brother 1. Flow cytometry showed decreased expression of SAP in CD4 (8%), CD8 (4%), and NK cells (47%). He met 5 of 8 criteria for HLH. He passed away despite treatment with gamifant and anakinra. Brother 3 is an 8-year-old fully vaccinated boy who also has the same pathogenic mutation in SH2D1A as both brothers. His immune workup was essentially normal except for a non-protective titer to tetanus toxoid. Flow cytometry for SAP showed slightly higher but low expression in CD4 (68%), CD8 (40%), and NK cells (86%). Conclusion Our case highlights the clinical variability of XLP-1 presentation in a family with the same pathogenic variant in SH2D1A. We conclude that the SH2D1A VUS is pathogenic and that SAP levels can correlate with severity of disease.
2024-04-19 | Case report: EBV-related eye orbits and sinuses lymphohistiocytic infiltration responsive to rituximab in a patient with X lymphoproliferative syndrome type 1.
X lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity due to mutations of SH2D1A, encoding for slam-associated protein (SAP). The clinical phenotype includes severe mononucleosis, hemophagocytic lymphohistiocytosis (HLH), and B-cell lymphomas. We report the case of a child affected with XLP1 who presented with an incomplete HLH, triggered by Epstein-Barr virus (EBV) and treated with rituximab, involving orbits and paranasal sinuses. The lesion was indistinguishable from lymphoma, complicating diagnosis and treatment. In addition, considering the high incidence of lymphoma in patients with XLP1, histology helped define its nature, driving therapeutic choices. We described an unusual presentation of incomplete HLH in a patient affected with XLP1: an EBV-driven infiltration of the orbits and paranasal sinuses. This led us to a challenging differential diagnosis of lymphoma-associated hemophagocytic syndrome, which can be frequently observed in patients with XLP1. Considering the extremely poor prognosis of this clinical finding, we sought for a prompt diagnosis and managed to obtain it and to immediately establish the right treatment on the basis of the pathological finding.
2023-09-25 | X-linked lymphoproliferative syndrome associated with Epstein-Barr virus encephalitis and lymphoproliferative disorder.
When treating patients with EBV encephalitis, the possibility of XLP should be considered. Once the diagnosis of XLP is made, aggressive treatment such as rituximab, and other immunosuppressive agents are desired for rapid transition to HSCT.
cell therapies
2026-08-22 | Genetic and autoimmune predispositions to fulminant viral hepatitis in children.
Fulminant viral hepatitis (FVH) in children is a rare but often fatal form of acute liver failure occurring in the absence of preexisting liver disease. Its exceptional incidence during otherwise common viral infections, including hepatitis A virus (HAV), hepatitis B virus (HBV), and herpes simplex virus (HSV), supports a decisive role for host susceptibility. Recent advances in human immunogenetics delineate two major, mechanistically distinct pathways to pediatric FVH. The first reflects failure of immune regulation, culminating in excessive IFN-γ-driven inflammation and immune-mediated hepatocellular necrosis. Autosomal recessive IL-18BP and IL-10RB deficiencies exemplify this mechanism, in which disruption of key regulatory checkpoints permits uncontrolled activation of cytotoxic lymphocytes and macrophage-dependent immunopathology, particularly in the context of HAV infection. The second pathway involves impaired intrinsic antiviral defense, most prominently through neutralizing autoantibodies against type I interferons, which phenocopy genetic defects of IFN-I signaling and are strongly associated with HSV-triggered FVH; in this setting, inadequate early antiviral control enables unchecked hepatic replication with extensive cytopathic damage. Finally, syndromic hyperinflammatory disorders, including familial hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease, broaden the spectrum of immune predisposition in which fulminant hepatitis may arise. Together, these discoveries redefine pediatric FVH as an immunopathological syndrome and provide a framework for targeted genetic and serologic diagnosis and for mechanism-based interventions aimed at improving survival.
2025-10-22 | The neurologic face of X-linked lymphoproliferative syndrome type 1: a systematic review.
BACKGROUND: X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity with high mortality rates. Neurological manifestations may be the presenting features and are often fatal; however, their characterization is insufficient, hindering optimal clinical management. The aim of this study is to systematically review the neurological characteristics, outcomes, and survival in XLP1 patients and identify parameters associated with improved prognosis. A PRISMA-guided analysis of PubMed, Web of Science, Scopus, and Embase (up to March 2025) identified studies documenting neurological involvement in genetically verified XLP1 patients. We extracted data on clinical features, neuroimaging findings, therapeutic interventions, and survival. RESULTS: We identified 42 genetically verified XLP1 patients with neurological involvement. Central nervous system (CNS) involvement comprised hemophagocytic lymphohistiocytosis (HLH) in 38.1%, vasculitis in 28.6%, and lymphoma in 19% of them. The development of brain vasculitis several months after Burkitt’s lymphoma was a specific presentation. The median age of neurological onset was 5 years. The predominant presenting symptoms were seizures (47.6%), altered consciousness (35.7%), and headaches (21.4%). Neuroimaging frequently revealed abnormalities in the temporal lobe and basal ganglia, often with hemorrhage and edema. Epstein-Barr virus (EBV) was identified in 54.8% of cases, sometimes limited to brain tissue. CSF analysis frequently showed elevated protein and pleocytosis. SH2D1A mutations were diverse, with Arg55 and Trp64 identified as recurrent hot spots. The overall mortality reached 52.4%, with most deaths occurring within five years of neurological onset. Conventional immunosuppressive and cytotoxic treatments were largely ineffective in changing the disease course. In exploratory analysis, hematopoietic stem cell transplantation (HSCT) did not significantly improve survival in the primary dataset, although sensitivity analysis suggested a possible benefit. CONCLUSIONS: Neurological involvement in XLP1 exhibits clinical heterogeneity and carries a high mortality rate. Early recognition and timely HSCT may improve survival, demonstrating the importance of vigilant neurological monitoring in affected individuals.
2025-05-22 | Targeting intracellular LMP2 with costimulatory signal-armed antibody-like TCR T cells.
Expanding the repertoire of CAR therapies to include intracellular antigens holds promise for treating a broad spectrum of malignancies. TCR-like T cells, capable of recognizing intracellular antigen-derived peptides in complex with HLA molecules (pHLA), represent a promising strategy in the field of engineered cellular therapy. This study introduced antibody-like TCR (abTCR) T cells that specifically targeted HLA-A*02:01-restricted LMP2426 peptides, a typical Epstein-Barr virus (EBV) latency II protein, for the treatment of EBV-associated lymphoproliferative diseases (EBV-LPDs). Compared with classic CAR T cells targeting the same epitope, abTCR T cells demonstrated superior efficiency, including increased CD107A expression, enhanced cytotoxicity, and elevated IFN-γ secretion, even when engaging with target cells that naturally present antigens. Moreover, a costimulatory signal-armed abTCR (Co-abTCR), which integrated a costimulatory structure with the abTCR, further enhanced the proliferation and in vivo tumoricidal efficacy of transfected T cells. Collectively, our study developed a potentially novel TCR-like T cell therapy that targets HLA-A*02/LMP2426 for the treatment of EBV-LPDs, providing a potential therapeutic solution for targeting of intracellular antigens in cancer immunotherapy.
2022-04-18 | Preemptive hematopoietic cell transplantation for asymptomatic patients with X-linked lymphoproliferative syndrome type 1.
Few reports have examined whether prophylactic allogeneic hematopoietic cell transplantation (HCT) for X-linked lymphoproliferative syndrome type 1 (XLP1) improves the prognosis. We compared the prognosis of symptomatic probands and affected siblings in the same family. Twenty-two cases (10 probands and 12 affected siblings) in Japan, the United Kingdom, and the United States were analyzed. The overall survival (OS) rate at 5 years after diagnosis was 70.0% in probands and 91.7% in affected siblings (p = 0.0789). The prognosis of patients who developed symptoms of XLP1 before HCT and those who did not was also compared. The 5-year probability of OS from the time of diagnosis in asymptomatic patients (100%) was significantly better than that in symptomatic patients (66.7%). These results suggested that early HCT as soon as the diagnosis is made improves the prognosis in asymptomatic XLP1 patients.
2022-01-05 | Two Clonally Distinct B-Cell Lymphomas Reveal the Diagnosis of XLP1 in a Male Child and His Asymptomatic Male Relatives: Case Report and Review of the Literature.
X-linked lymphoproliferative disease type 1 (XLP1) is a primary immunodeficiency disorder caused by pathogenic variants in the SH2D1A gene (SH2 domain containing protein 1A). Patients with XLP1 may present acutely with fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, and/or B-cell non-Hodgkin lymphoma (B-NHL). We report a boy who developed 2 clonally distinct B-NHL 4 years apart and was found to have previously unrecognized XLP1. The report highlights the importance of clonal analysis and XLP1 testing in males with presumed late recurrences of B-NHL, and the role of allogeneic stem cell transplant (allo-SCT) in XLP1 patients and their affected male relatives.
other
2026-01-08 | Polyclonal evolution of lymphoproliferative disorders in XLP1
X-linked lymphoproliferative syndrome type 1 (XLP1) is an inborn error of immunity caused by pathogenic variants in SH2D1A and is frequently complicated by Epstein-Barr virus (EBV)–associated lymphoproliferative disorders (LPDs). However, cases of LPD without EBV infection have been reported and remain poorly understood. We investigated tumorigenesis mechanisms through transcriptomic profiling and somatic variant analysis in tumor samples from six patients with XLP1. Pathogenic variants were identified in two: one developed two distinct LPDs harboring CARD11/GNA13 and MECOM variants, while the other carried IRF4, P2RY8, KRAS, and CCND3 variants. Transcriptome analysis of three tumors, compared with diffuse large B cell lymphoma from patients without an underlying immune defect, revealed a distinct expression profile. Gene Ontology analysis showed upregulation of adaptive immune response genes, including various IgH and TCR genes, suggesting polyclonal lymphocyte proliferation. Overall, LPD associated with XLP1 may originate from polyclonal lymphocyte expansion, either in the presence or absence of EBV infection, and subsequently progress to malignancy through somatic variants.
2025-06-27 | X-linked lymphoproliferative disease type 1: a clinical and genetic update.
X-linked lymphoproliferative disease (XLP), also known as Duncan's disease, is a primary immunodeficiency disorder linked to the X chromosome. In 1998, SH2D1A, which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), was identified as the first pathogenic gene associated with XLP. To date, more than 100 mutation sites in this gene have been documented. The disease is associated with infection with Epstein-Barr virus (EBV) and characterized by hemophagocytic lymphohistiocytosis (HLH), hypogammaglobulinemia, and lymphomas. Pathogenesis is intricately associated with cell type-specific SAP-SLAM signaling pathways. Particularly, the immune cell defects involve impaired T cell-B cell interactions, reduced cytotoxicity of Natural Killer (NK) cells, and abnormal development of Natural Killer T (NKT) cells. These factors collectively increase susceptibility to EBV and drive clinical manifestations in XLP type 1 (XLP1) patients. Although establishing a definitive correlation between specific genotypes and clinical phenotypes remains challenging, emerging evidence suggests a potential association. This underscores the critical need for further large-scale studies to elucidate this relationship. Given the current understanding of the pathophysiological mechanisms associated with XLP1, specific treatments to normalize SAP expression and restore immune tolerance in XLP1 patients play an important role. In addition to the necessity for long-term studies to verify the efficacy and safety of hematopoietic stem cell transplantation (HSCT), gene therapies currently under development, along with other emerging treatments, exhibit substantial promise for future clinical applications.
2023-02-03 | Lentiviral Gene Transfer Corrects Immune Abnormalities in XIAP Deficiency.
X-linked inhibitor of apoptosis protein (XIAP) deficiency is a severe immunodeficiency with clinical features including hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD) due to defective NOD2 responses. Management includes immunomodulatory therapies and hematopoietic stem cell transplant (HSCT). However, this cohort is particularly susceptible to the chemotherapeutic regimens and acutely affected by graft-vs-host disease (GvHD), driving poor long-term survival in transplanted patients. Autologous HSC gene therapy could offer an alternative treatment option and would abrogate the risks of alloreactivity. Hematopoietic progenitor (Lin-ve) cells from XIAPy/- mice were transduced with a lentiviral vector encoding human XIAP cDNA before transplantation into irradiated XIAP y/- recipients. After 12 weeks animals were challenged with the dectin-1 ligand curdlan and recovery of innate immune function was evaluated though analysis of inflammatory cytokines, body weight, and splenomegaly. XIAP patient-derived CD14+ monocytes were transduced with the same vector and functional recovery was demonstrated using in vitro L18-MDP/NOD2 assays. In treated XIAPy/- mice, ~40% engraftment of gene-corrected Lin-ve cells led to significant recovery of weight loss, splenomegaly, and inflammatory cytokine responses to curdlan, comparable to wild-type mice. Serum IL-6, IL-10, MCP-1, and TNF were significantly reduced 2-h post-curdlan administration in non-corrected XIAPy/- mice compared to wild-type and gene-corrected animals. Appropriate reduction of inflammatory responses was observed in gene-corrected mice, whereas non-corrected mice developed an inflammatory profile 9 days post-curdlan challenge. In gene-corrected patient CD14+ monocytes, TNF responses were restored following NOD2 activation with L18-MDP. Gene correction of HSCs recovers XIAP-dependent immune defects and could offer a treatment option for patients with XIAP deficiency.
2021-06-22 | T cell gene therapy to treat immunodeficiency.
The application of therapeutic T cells for a number of conditions has been developed over the past few decades with notable successes including donor lymphocyte infusions, virus-specific T cells and more recently CAR-T cell therapy. Primary immunodeficiencies are monogenetic disorders leading to abnormal development or function of the immune system. Haematopoietic stem cell transplantation and, in specific candidate diseases, haematopoietic stem cell gene therapy has been the only definitive treatment option so far. However, autologous gene-modified T cell therapy may offer a potential cure in conditions primarily affecting the lymphoid compartment. In this review we will highlight several T cell gene addition or gene-editing approaches in different target diseases with a focus on what we have learnt from clinical experience and promising preclinical studies in primary immunodeficiencies. Functional T cells are required not only for normal immune responses to infection (affected in CD40 ligand deficiency), but also for immune regulation [disrupted in IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-Linked) due to dysfunctional FOXP3 and CTLA4 deficiency] or cytotoxicity [defective in X-lymphoproliferative disease and familial haemophagocytic lymphohistiocytosis (HLH) syndromes]. In all these candidate diseases, restoration of T cell function by gene therapy could be of great value.
2019-08-02 | Transfer of gene-corrected T cells corrects humoral and cytotoxic defects in patients with X-linked lymphoproliferative disease.
X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell-dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia. Curative treatment is limited to hematopoietic stem cell transplantation, with outcomes reliant on a good donor match. Because most symptoms arise from defective T-cell function, we investigated whether transfer of SAP gene-corrected T cells could reconstitute known effector cell defects. CD3+ lymphocytes from Sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sublethally irradiated Sap-deficient recipients. After immunization with the T-dependent antigen 4-hydroxy-3-nitrophenylacetly chicken gammaglobulin (NP-CGG), recovery of humoral function was evaluated through germinal center formation and antigen-specific responses. To efficiently transduce CD3+ cells from patients, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated by using in vitro cytotoxicity and T follicular helper cell function assays alongside tumor clearance in an in vivo lymphoblastoid cell line lymphoma xenograft model. In Sap-deficient mice 20% to 40% engraftment of gene-modified T cells led to significant recovery of germinal center formation and NP-specific antibody responses. Gene-corrected T cells from patients demonstrated improved cytotoxicity and T follicular helper cell function in vitro. Adoptive transfer of gene-corrected cytotoxic T lymphocytes from patients reduced tumor burden to a level comparable with that seen in healthy donor cytotoxic T lymphocytes in an in vivo lymphoma model. These data demonstrate that autologous T-cell gene therapy corrects SAP-dependent defects and might offer an alternative therapeutic option for patients with X-linked lymphoproliferative disease 1.
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