X-linked Lymphoproliferative Syndrome Type Research Articles

Single-Cell Transcriptomic Analysis of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis.

Epstein-Barr virus (EBV) infection can lead to infectious mononucleosis (EBV-IM) and, more rarely, EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which is characterized by a life-threatening hyperinflammatory cytokine storm with immune dysregulation. Interferon-gamma (IFNγ) has been identified as a critical mediator for primary HLH; however, the detailed role of IFNγ and other cytokines in EBV-HLH is not fully understood. In this study, we used single-cell RNA sequencing to characterize the immune landscape of EBV-HLH and compared it with EBV-IM. Three pediatric patients with EBV-HLH with different backgrounds,one with X-linked lymphoproliferative syndrome type 1 (XLP1), two with chronic active EBV disease (CAEBV), and two patients with EBV-IM were enrolled. The TUBA1B + STMN1 + CD8 + T cell cluster, a responsive proliferating cluster with rich mRNA detection, was explicitly observed in EBV-IM, and the upregulation of SH2D1A-the gene responsible for XLP1-was localized in this cluster. This proliferative cluster was scarcely observed in EBV-HLH cases. In EBV-HLH cases with CAEBV, upregulation of LAG3 was observed in EBV-infected cells, which may be associated with an impaired response by CD8 + T cells. Additionally, genes involved in type I interferon (IFN) signaling were commonly upregulated in each cell fraction of EBV-HLH, and activation of type II IFN signaling was observed in CD4 + T cells, natural killer cells, and monocytes but not in CD8 + T cells in EBV-HLH. In conclusion, impaired responsive proliferation of CD8 + T cells and upregulation of type I IFN signaling were commonly observed in EBV-HLH cases, regardless of the patients' background, indicating the key features of EBV-HLH.

Clinical Case of X-Linked Lymphoproliferative Syndrome Burdened with Hemophagocytic Lymphohistiocytosis and Crohn's Disease

Background. X-linked lymphoproliferative (XLP) syndrome is hereditary disease with the incidence of 1-3 per 1 million born boys. This clinical case demonstrates a rare picture of XLP type 2 manifestation without prior Epstein-Barr virus.Clinical case description. Boy D., 15 years old, was admitted to Morozovskaya Children's City Hospital with complaints on fever, abdominal pain, loose stools, weight loss. The past medical history included hemophagocytic syndrome (remission) and acute erythema nodosum. We have performed several studies: abdominal ultrasound (hepatomegaly, dynamic changes in the intestine: parts of the small intestine were enlarged and walls were thickened, mass peristalsis, walls of transverse colon and descending colon are thickened up to 5 mm, mesenteric lymphadenopathy), rectosigmoidoscopy (high-activity ulcerative proctosigmoiditis corresponds to Crohn's disease), biochemical and clinical blood tests (active hemophagocytic syndrome), coagulogram (secondary hypocoagulation), myelogram (no data on hemoblastosis or aplastic condition). Virological blood tests (CMV, EBV, HHV-VI): negative. Laboratory and instrumental tests have revealed recurrence of hemophagocytic syndrome and Crohn's disease. The child was consulted by rheumatologist, hematologist, gastroenterologist, geneticist, neurologist, and clinical pharmacologist. The primary immune deficiency disease was suspected in this patient due to his medical history. Molecular genetic study was performed (deletion including the XIAP gene was revealed) and the diagnosis of primary immune deficiency was verified: X-linked lymphoproliferative syndrome type 2. Thus, allogeneic haematopoietic stem cell transplantation (HSCT) was performed.Conclusion. XLP diagnosis and management require multidisciplinary approach. The early diagnosis is crucial due to the high risk of secondary complications development that can significantly worsen the disease's prognosis. Allogeneic HSCT is the only effective treatment for the disease.

370 - The importance of early detection in x-linked lymphoproliferative syndrome type 1: the story of three family members

370 - The importance of early detection in x-linked lymphoproliferative syndrome type 1: the story of three family members

Immune-mediated inflammatory diseases with chronic excess of serum interleukin-18.

Review: Interleukin-18 (IL-18) is a proinflammatory cytokine that promotes various innate immune processes related to infection, inflammation, and autoimmunity. Patients with systemic juvenile idiopathic arthritis and adult-onset Still’s disease exhibit chronic excess of serum IL-18, which is associated with a high incidence of macrophage activation syndrome (MAS), although the mechanisms of IL-18 regulation in such diseases remain largely unknown. Similar elevation of serum IL-18 and susceptibility to MAS/hemophagocytic lymphohistiocytosis (HLH) have been reported in monogenic diseases such as X-linked inhibitor of apoptosis deficiency (i.e., X-linked lymphoproliferative syndrome type 2) and NLRC4-associated autoinflammatory disease. Recent advances in molecular and cellular biology allow the identification of other genetic defects such as defects in CDC42, PSTPIP1, and WDR1 that result in high serum IL-18 levels and hyperinflammation. Among these diseases, chronic excess of serum IL-18 appears to be linked with severe hyperinflammation and/or predisposition to MAS/HLH. In this review, we focus on recent findings in inflammatory diseases associated with and probably attributable to chronic excess of serum IL-18 and describe the clinical and therapeutical relevance of understanding the pathology of this group of diseases.

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.

Delayed Diagnosis of X-linked Lymphoproliferative Syndrome Type 2 in a 17-year-old Male With Severe Crohn’s Disease and Recurrent Skin Infections

X-linked lymphoproliferative syndrome type 2 (XLP2) is a rare genetic primary immunodeficiency disease caused by mutations in the XIAP gene that lead to deficiency of the X-linked inhibitor of apoptosis protein. XLP2 is characterized by dysregulated immune responses and can result in an inflammatory bowel disease (IBD)-like phenotype, a form of monogenic IBD. Patients with XLP2 often succumb to fulminant hemophagocytic lymphohistiocytosis or Epstein-Barr virus infections. Hematopoietic stem cell transplantation (HSCT) is currently the only definitive treatment for XLP2. We report an adolescent with a delayed diagnosis of XLP2 in the setting of severe Crohn’s disease diagnosed at age 9 years and recurrent skin infections. He is under evaluation for HSCT. Gastroenterologists must recognize monogenic IBD in patients of all ages with severe disease and signs of an underlying primary immunodeficiency disease. Patients with suspected monogenic IBD should undergo immunologic and genetic analysis at diagnosis to initiate potentially life-saving treatment.

Infection-induced inflammation from specific inborn errors of immunity to COVID-19.

Inborn errors of immunity (IEIs) are a group of genetically defined disorders leading to defective immunity. Some IEIs have been linked to mutations of immune receptors or signaling molecules, resulting in defective signaling of respective cascades essential for combating specific pathogens. However, it remains incompletely understood why in selected IEIs, such as X‐linked lymphoproliferative syndrome type 2 (XLP‐2), hypo‐immune response to specific pathogens results in persistent inflammation. Moreover, mechanisms underlying the generation of anticytokine autoantibodies are mostly unknown. Recently, IEIs have been associated with coronavirus disease 2019 (COVID‐19), with a small proportion of patients that contract severe COVID‐19 displaying loss‐of‐function mutations in genes associated with type I interferons (IFNs). Moreover, approximately 10% of patients with severe COVID‐19 possess anti‐type I IFN‐neutralizing autoantibodies. Apart from IEIs that impair immune responses to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), SARS‐CoV‐2 encodes several proteins that suppress early type I IFN production. One primary consequence of the lack of type I IFNs during early SARS‐CoV‐2 infection is the increased inflammation associated with COVID‐19. In XLP‐2, resolution of inflammation rescued experimental subjects from infection‐induced mortality. Recent studies also indicate that targeting inflammation could alleviate COVID‐19. In this review, we discuss infection‐induced inflammation in IEIs, using XLP‐2 and COVID‐19 as examples. We suggest that resolving inflammation may represent an effective therapeutic approach to these diseases.

Immune dysregulation symptoms as a rare manifestation of X-linked lymphoproliferative syndrome type 1

X-linked lymphoproliferative syndrome type 1 (XLP1) is a primary immunodeficiency, the most dramatic manifestations of which are hemophagocytic lymphohistiocytosis (usually associated with Epstein-Barr virus), lymphoma and dysgammaglobulinemia. Immune symptoms like vasculitis, aplastic anemia and others are extremely rare. Specialists awareness and suspicion regarding such complications of XLP1 facilitate correct diagnosis and early curative treatment - hematopoietic stem cell transplantation (HSCT). Here we present two clinical cases of XLP1 with immune dysregulation symptoms where one patient underwent successful HSCT. In each case, the parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

Verification of X-linked lymphoproliferative syndrome type 1 and 2 using a flow cytometry method

Х-linked lymphoproliferative syndrome (XLP) is a life-threatening primary immunodeficiency, characterized by hemophagocytic lymphohistiocytosis, lymphoproliferation and hypogammaglobulinemia. The most frequent forms of XLP – XLP1 and XLP2 – are caused by mutations of the SH2D1A and BIRС4/XIAP genes, coding for SAP and XIAP proteins, respectively. Early diagnosis is important as it allows to prevent severe complications by introducing specific therapy and proceed to hematopoietic stem cell transplantation. Here we describe validation of precise and fast flow cytometry-based method of XLP1 and XLP2 laboratory diagnostics. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. 89 patients from 2 months to 18 years of age seen at our Center from July 2016 to February 2020 with symptoms suspicious of XLP were included in the study. Decrease of SAP intracellular expression was found in 9 patients, and XIAP – in 10 patients. In all of them XLP diagnosis was confirmed by detection of SH2D1A or XIAP mutations, respectively. Female mutations carries from the families of these patients demonstrated abnormal expression of respective proteins. Analysis of the data allowed to calculated the optimized cut-off numbers for the SAP and XIAP expression, which was 50% and 80% in T lymphocytes (respectively) and 45% и 75% in NK lymphocytes (respectively). Specificity and sensitivity of the method was 100% for both proteins. Therefore the method of assessment of SAP and XIAP intracellular expression via flow cytometry allows fast and precise diagnostics of XLP1 and XLP2.

Haematological complications of X-linked lymphoproliferative syndrome type 1 and 2

X-linked lymphoproliferative syndrome type 1 (XLP1) and 2 (XLP2) are primary immunodeficiencies (PID), combined in one group because of shared abnormal response to Epstein–Barr virus (EBV) and caused by mutations in SH2D1A and XIAP genes, respectively. Hemophagocytic lymphohistiocytosis (HLH) is a frequent life-threatening complication of both diseases. We analyzed haematological complications, such as HLH and cytopenia, in 12 patients with XLP1 and 11 – with XLP2. The research was approved by Independent ethic committee and the academic board of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia). Analyzed were patients who were treated or consulted in Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia) since 2012 and in Russian Clinical Children's Hospital (Moscow, Russia) since 2003 to February 2020. 19 XLP1 patients from 13 families and 16 XLP2 patients from 14 families were included. For patients with haematological complications XLP diagnosis was based on the ESID criteria and genetically confirmed in 19 cases by detecting mutations in SH2D1A or XIAP gene (8 XLP1 and 11 XLP2 patients). Intracellular expression of corresponding SAP and XIAP proteins was performed by intracellular staining of SAP/XIAP in lymphocytes. Genetic analysis to detect mutations in SH2D1A and XIAP genes was performed by the Sanger sequencing method on Genetic Analyzer 3130х1 (Applied Biosystems, USA) according to the manufacturer protocol, or by the Multiplex Ligation-Dependent Probe Amplification method using SALSA MLPA Probemix P205 SH2D1A-XIAP-ITK (MRC-Holland, the Netherlands), or by the next-generation sequencing (NGS) method on NextSeq (Illumina) platform using a paired end tag (PET) sequencing method. Varying degree of cytopenia was present in 4 patients with XLP1 and 2 – with XLP2. None of XLP1 patients with cytopenia, and all XLP2 patients with cytopenia subsequently developed full HLH. Overall 8 XLP1 and 11 XLP2 patients developed HLH. HLH-associated mortality before hematopoietic stem cell transplantation (HSCT) was 75% in a group of XLP1 patients and 0% – in XLP2. HSCT was performed in 3 XLP1 patients, which was not sufficient for survival analysis and in 9 XLP2 patients, in whom overall survival was 74%. HLH is the most often haematological complication of XLP1 and XLP2. Fulminant HLH in XLP1 requires early and aggressive treatment. In XLP2 patients HLH remission can be reached on mono- or bicomponent immunosuppressive therapy which allows to reduce therapy-associated toxicity. In XLP2 patients cytopenia can precede HLH, while in XLP1 patients cytopenia is probably caused by other mechanisms. HSCT is a curative treatment for XLP1 and 2 which should be considered as soon as the diagnosis is made.

Haploidentical Hematopoietic Stem Cell Transplantation for XIAP Deficiency: a Single-Center Report.

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in the XIAP/BIRC4 gene is a rare inherited primary immunodeficiency also known as X-linked lymphoproliferative syndrome type 2 (XLP2). Hematopoietic stem cell transplantation (HSCT) is currently the only curative strategy available. However, few studies of haploidentical HSCT have been published regarding the outcomes in patients with this syndrome. We evaluated the XIAP gene analysis and clinical characteristics of four Chinese patients with XIAP who underwent haploidentical HSCT. The mutations in the two of four patients had not yet been reported in the literature. All of the patients had recurrent hemophagocytic lymphohistiocytosis but did not have a good matched donor and underwent haploidentical HSCT at BCH in China between September 2016 and December 2018. All four patients received antithymocyte globulin with fludarabine-based regimens. Two patients underwent reduced intensity conditioning (RIC), and the other two received modified myeloablative conditioning (MAC) regimens. Three of the four patients survived. Three patients experienced complications with mixed chimerism. One of the four patients who underwent RIC had early graft loss and then developed grade IV acute graft-versus-host disease (GVHD) after donor lymphocyte infusion with bone marrow. The two patients who received MAC survived with no or mild GVHD, even though one of them developed hepatic veno-occlusive disease in the early stage of transplantation. Haploidentical HSCT may be a treatment option for patients with XIAP deficiency who lack a good matched donor. More studies are needed to determine whether modified MAC with reduced toxicity is more suitable for haploidentical transplantation.

Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn\u2019s disease

X-linked inhibitor of apoptosis (XIAP) is the most potent human inhibitor of apoptosis, and is also involved in NOD2-dependent NFκB and MAPK signalling cascade activation. The absence or defective function of XIAP leads to the development of a rare and severe primary immunodeficiency known as X-linked lymphoproliferative syndrome type 2 (XLP-2), which is characterized by a triad of clinical manifestations, including a high incidence of haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and inflammatory bowel disease (IBD), usually with very early onset. Here, we present a novel XIAP mutation identified in a patient with atypical adult-onset IBD complicated by relapsing HLH, splenomegaly and sarcoid-like disease. The c.266delA mutation in the XIAP gene creates a premature stop codon, and causes a severe reduction in XIAP protein expression. The mutation is also associated with impaired spontaneous and staurosporine- and PMA-induced apoptosis accompanied by significantly increased expression of pro-apoptotic genes. We also confirmed the negative impact of this particular XIAP mutation on NOD2-dependent NFκB and MAPK activation, while NOD2-independent activation was found to be unaffected. Moreover, we assume that the mutation has an impact on the overproduction of IL-12 and IFNγ, the shift towards the Th1 immune response and increased numbers of central memory and effector memory CD4+ and CD8+ T cells. All these changes contribute to immune dysregulation and the clinical manifestation of XLP-2.

P091 XIAP MUTATION IS ASSOCIATED WITH TREATMENT RESISTANT CROHN’S DISEASE: A SINGLE INSTITUTION CASE SERIES

Abstract Background X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), occurs in about 1 in 5 million males [1] and is associated with development of hemophagocytic lymphohistiocytosis (HLH), splenomegaly and treatment-resistant Crohn’s disease [2][3]. Here we present the cases of two XLP2 siblings with lymphopenia, hepatosplenomegaly, recurrent infections, and refractory Crohn’s disease. Case Discussions The first brother was diagnosed with ileocolonic Crohn’s disease at age 8. Lymphopenia and hepatomegaly were present at the time of diagnosis. Initial management with azathioprine resulted in response, but not remission so was switched to MTX. After a year on MTX, CT abd/pelvis demonstrated hepatosplenomegaly concerning for lymphoma. Bone marrow aspiration was remarkable for decreased B-cells without blasts. Liver biopsy demonstrated only sinusoidal dilation. Patient was switched to infliximab + prednisone, but required right hemicolectomy for TI stricture soon after initiation. While on anti-TNF, he suffered multiple viral and bacterial infections, as well as severe psoriasis which did not abate after removing anti-TNF therapy. His CD progressed despite trials of vedolizumab and certolizumab. He underwent diversion loop ileostomy for persistent disease and initiated ustekinumab + MTX. His CD symptoms and psoriatic rash have improved on ustekinumab, but neither are in remission. He still suffers multiple skin infections and infection-induced leukopenia. His most recent immunology evaluation revealed XIAP mutation based on molecular genetic testing, consistent with XLP2. He has been improving with IVIG. The second brother presented with hepatosplenomegaly in infancy, work-up was unrevealing. He was plagued by recurrent infections, lymphopenia, and hepatosplenomegaly throughout childhood. Soon after his CD diagnosis at age 16, bone marrow aspiration for hepatosplenomegaly was remarkable only for low B-cells. A year later, he underwent diverting loop ileostomy for worsening symptoms. At age 20, he underwent APR with left hemicolectomy/end transverse colostomy. He failed multiple medications including prednisone, infliximab, adalimumab, and vedolizumab. He was recently switched to ustekinumab + MTX and has symptomatically improved. He was referred to our immunologist, who suspects XIAP mutation based on his sibling’s diagnosis and has since begun IVIG. Discussion XLP2 is a rare disease that can be challenging to diagnose due to variance in clinical presentation. In this series, our patients presented with refractory, early-onset CD most likely due to XIAP mutation. XIAP deficiency should be suspected in treatment resistant early-onset Crohn’s disease, especially if complicated by recurrent infections or unexplained hepatosplenomegaly. Ustekinumab combined with methotrexate has demonstrated benefit in their CD management, and should be considered in the management of CD associated with XIAP deficiency.

P091 XIAP MUTATION IS ASSOCIATED WITH TREATMENT RESISTANT CROHN’S DISEASE: A SINGLE INSTITUTION CASE SERIES

X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), occurs in about 1 in 5 million males [1] and is associated with development of hemophagocytic lymphohistiocytosis (HLH), splenomegaly and treatment-resistant Crohn’s disease [2][3]. Here we present the cases of two XLP2 siblings with lymphopenia, hepatosplenomegaly, recurrent infections, and refractory Crohn’s disease.

Inherited lymphoproliferative disorders

Lymphoproliferative disorders (LPDs) are caused by dysregulated lymphocyte proliferation and include polyclonal benign and monoclonal malignant diseases. LPDs frequently occur in immunocompromized patients, particularly those with primary immunodeficiency disease (PID), a monogenic disease. PID-associated LPD corresponds to inherited LPD. Here, we describe inherited LPD and focus on IKZF1-associated diseases and Epstein-Barr virus-associated LPD, such as ZAP70 deficiency and X-linked lymphoproliferative syndrome type 1 with somatic reversion mosaicism. Disclosing the pathogenesis of inherited LPDs would lead to a broad understanding of LPDs and development of new treatment strategies.

Hematopoietic cell transplantation for asymptomatic X-linked lymphoproliferative syndrome type 1

BackgroundX-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immune deficiency, which is caused by SH2D1A gene mutations. XLP1 is commonly associated with Epstein–Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphoma. The only curative treatment for XLP1 is allogeneic hematopoietic cell transplantation. However, published data detailing the clinical course of, and indications for, allogeneic hematopoietic cell transplantation in asymptomatic patients with XLP1 is lacking. Although relevant family history could be useful in identifying patients with XLP1 before disease onset, no guidelines have been established on the management of asymptomatic patients with XLP1. Therefore, clinicians and families face dilemmas in balancing between the risk of waiting for the disease onset, and the risk of transplant-related mortality associated with allogeneic hematopoietic cell transplantation, which is often performed at a very young age. We first describe the detailed clinical course of an asymptomatic patient with XLP1 who successfully underwent allogeneic hematopoietic cell transplantation.Case presentationA boy was born at 39 weeks of gestation, weighing 3016 g at birth. He appeared fine, but he underwent genetic testing because his maternal cousin had XLP1. He was found to have a novel c.207_208insC (p.Pro70ProfsX4) mutation in exon 3 of SH2D1A, which was also found in his cousin. There was no HLA-identical donor in his family. Immunoglobulin was administered monthly to prevent EBV infection while searching for an alternative donor. He underwent allogeneic bone marrow transplantation (BMT) from an allele HLA 8/8 fully matched, unrelated donor with a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, melphalan, and low-dose total body irradiation (TBI) at 20 months of age. The patient has been doing well for 2 years post transplantation and maintaining complete donor chimerism without any evidence of chronic graft versus host disease.ConclusionsWe describe a case of an asymptomatic patient with XLP1, who successfully underwent unrelated BMT with RIC regimen consisting of fludarabine, melphalan, and 3 Gy TBI. That was well tolerated and successfully generated complete chimerism in every subpopulation. This case delineates the option of allogeneic hematopoietic cell transplantation even in asymptomatic patients with XLP1.

Modification of cellular and humoral immunity by somatically reverted T cells in X-linked lymphoproliferative syndrome type 1

Modification of cellular and humoral immunity by somatically reverted T cells in X-linked lymphoproliferative syndrome type 1

Identification of a novel nonsense mutation in SH2D1A in a patient with X-linked lymphoproliferative syndrome type 1: a case report

BackgroundX-linked lymphoproliferative syndrome type 1 (XLP1) is an X-linked recessive genetic disorder with a strong resemblance to hemophagocytic lymphohistiocytosis (HLH). Causative mutations for XLP1 have been identified in SH2D1A, located on chromosome Xq25.Case presentationWe report a case of an 18-month-old male with a novel nonsense mutation in SH2D1A. The patient presented the typical phenotype of HLH, including splenomegaly and hemophagocytosis in the bone marrow. Thus, he was initially diagnosed with HLH based on HLH-2004 guidelines. High-throughput amplicon sequencing was performed to detect mutations in the most commonly reported causative genes of HLH, i.e., PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP. A likely pathogenic nonsense mutation was detected in SH2D1A (NM_002351.4:c.300T>A). The mutation was inherited from the patient’s mother, and an X-linked recessive mode of inheritance was confirmed by a two-generation pedigree analysis based on Sanger sequencing results.ConclusionsThe nonsense mutation in SH2D1A (NM_002351.4:c.300T>A) was reported for the first time in a case of XLP1 and was considered to be likely pathogenic based on the truncation of the mRNA sequence. This finding expands the spectrum of known XLP-related mutations in Chinese patients and indicates the utility of amplicon sequencing for XLP and HLH diagnosis.

IL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells

X-linked lymphoproliferative syndrome type-2 (XLP-2) is a primary immunodeficiency disease attributed to XIAP mutation and is triggered by infection. Here, we show that mouse Xiap−/− regulatory T (Treg) cells and human XIAP-deficient Treg cells are defective in suppressive function. The Xiap−/− Treg cell defect is linked partly to decreased SOCS1 expression. XIAP binds SOCS1 and promotes SOCS1 stabilization. Foxp3 stability is reduced in Xiap−/− Treg cells. In addition, Xiap−/− Treg cells are prone to IFN-γ secretion. Transfer of wild-type Treg cells partly rescues infection-induced inflammation in Xiap−/− mice. Notably, inflammation-induced reprogramming of Xiap−/− Treg cells can be prevented by blockade of the IL-6 receptor (IL-6R), and a combination of anti-IL-6R and Xiap−/− Treg cells confers survival to inflammatory infection in Xiap−/− mice. Our results suggest that XLP-2 can be corrected by combination treatment with autologous iTreg (induced Treg) cells and anti-IL-6R antibody, bypassing the necessity to transduce Treg cells with XIAP.

Successful rituximab treatment of a patient with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis accompanied by X-linked lymphoproliferative syndrome type 1

Successful rituximab treatment of a patient with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis accompanied by X-linked lymphoproliferative syndrome type 1