Advances in autoimmune lymphoproliferative syndromes. Madkaikar Manisha,Mhatre Snehal,Gupta Maya,Ghosh Kanjaksha European journal of haematology Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis. It is characterized by non-malignant lymphoproliferation autoimmunity mostly directed toward blood cells and increased risk of lymphoma. Majority of patients with ALPS harbor heterozygous germline mutations in the gene for the TNF receptor-family member Fas (CD 95, Apo-1) which are inherited in an autosomal dominant fashion. Somatic Fas mutations are the second most common genetic etiology of ALPS. Additionally mutations in the genes encoding Fas-ligand (FASLG), caspase 10 (CASP10) and caspase 8 (CASP8), NRAS and KRAS have been identified in a small number of patients with ALPS and related disorders. Approximately one-third of patients with ALPS have yet unidentified defect. ALPS was initially thought to be a very rare disease, but recent studies have shown that it may be more common than previously thought. Testing for ALPS should therefore be considered in patients with unexplained lymphadenopathy, cytopenias, and hepatosplenomegaly. There have been significant advances in the understanding of the pathophysiology of ALPS in last few years which has resulted in the development of new diagnostic criteria and a number of targeted therapies. This review describes the clinical and laboratory manifestations found in patients with ALPS, as well as the molecular basis for the disease and new advances in treatment. 10.1111/j.1600-0609.2011.01617.x
    Atypical presentation of autoimmune lymphoproliferative syndrome due to CASP10 mutation. Tripodi Serena Ilaria,Mazza Cinzia,Moratto Daniele,Ramenghi Ugo,Caorsi Roberta,Gattorno Marco,Badolato Raffaele Immunology letters Herein we describe the case of a 8-years-old boy with diagnosis of atypical autoimmune lymphoproliferative syndrome (ALPS), carrying heterozygous mutation of CASP10 gene (I406L). He presented with multiple non-invasive infections of the skin, that were associated to chronic non-malignant non-infectious lymphadenopathy, failure to thrive, weakness, arthralgia, relapsing oral aftosis, and expansion of TCRαβ(+) CD4(-)/CD8(-) T cells. This observation suggests that cutaneous infections can be observed in ALPS patients carrying CASP10 mutations. 10.1016/j.imlet.2016.07.001
    FAS-mediated apoptosis impairment in patients with ALPS/ALPS-like phenotype carrying variants on CASP10 gene. Miano Maurizio,Cappelli Enrico,Pezzulla Agnese,Venè Roberta,Grossi Alice,Terranova Paola,Palmisani Elena,Maggiore Rosario,Guardo Daniela,Lanza Tiziana,Calvillo Michaela,Micalizzi Concetta,Pierri Filomena,Vernarecci Chiara,Beccaria Andrea,Corsolini Fabio,Lanciotti Marina,Russo Giovanna,Ceccherini Isabella,Dufour Carlo,Fioredda Francesca British journal of haematology Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to  other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10-mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS-like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS-ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS-like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype. 10.1111/bjh.16098
    Autoimmune lymphoproliferative syndrome due to somatic FAS mutation (ALPS-sFAS) combined with a germline caspase-10 (CASP10) variation. Martínez-Feito Ana,Melero Josefa,Mora-Díaz Sergio,Rodríguez-Vigil Carmen,Elduayen Ramón,González-Granado Luis I,Pérez-Méndez Dolores,Sánchez-Zapardiel Elena,Ruiz-García Raquel,Menchén Miguela,Díaz-Madroñero Josefa,Paz-Artal Estela,Del Orbe-Barreto Rafael,Riñón Marta,Allende Luis M Immunobiology Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency caused by impaired Fas/FasL-mediated apoptosis of lymphocytes and is characterized by chronic nonmalignant or benign lymphoproliferation, autoimmune manifestations and expansion of double negative (DN) T-cells (TCRαβ+CD4-CD8-). Most cases of ALPS are associated with germline (ALPS-FAS) or somatic (ALPS-sFAS) heterozygous FAS mutations or a combination of both. Here we report three unrelated patients with ALPS-sFAS. Only one of them showed impaired Fas function in PHA-activated T-cells. In this patient, the genetic analysis of the caspase-10 gene (CASP10) identified a heterozygous germline change in exon 9 (c.1337A>G) causing Y446C substitution in the caspase-10 protein. In addition, this patient had a dysregulated T- and B-cell phenotype; circulating lymphocytes showed expansion of T effector memory CD45RA+ (TEMRA) CD4 T-cells, effector memory CD8 T-cells, CD21(low) B-cells and reduced memory switched B-cells. Additionally, this patient showed altered expression in T-cells of several molecules that change during differentiation from naïve to effector cells (CD27, CD95, CD57 and perforin). Molecular alterations in genes of the Fas pathway are necessary for the development of ALPS and this syndrome could be influenced by the concurrent effect of other mutations hitting different genes involved in Fas or related pathways. 10.1016/j.imbio.2015.08.004
    Decreased activation-induced cell death by EBV-transformed B-cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation. Ruiz-García Raquel,Mora Sergio,Lozano-Sánchez Gema,Martínez-Lostao Luis,Paz-Artal Estela,Ruiz-Contreras Jesús,Anel Alberto,González-Granado Luis I,Moreno-Pérez David,Allende Luis M Pediatric research BACKGROUND:Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency characterized by chronic lymphoproliferation, autoimmune manifestations, expansion of double-negative T-cells, and susceptibility to malignancies. Most cases of ALPS are caused by germline or somatic FAS mutations. We report the case of an ALPS patient due to a novel homozygous Fasligand gene mutation (ALPS-FASLG). METHODS:ALPS biomarkers were measured and FASLG mutation was identified. Functional characterization was carried out based on activation-induced cell death (AICD) and cytotoxicity assays. RESULTS:This report describes the cases of a patient who presented a severe form of ALPS-FASLG, and his brother who had died due to complications related to ALPS. Moreover, in another family, we present the first case of lymphoma in a patient with ALPS-FASLG. Functional studies showed defective Fasligand-mediated apoptosis, cytotoxicity, and AICD in T-cell blasts. Otherwise, expression of the FASLG gene and corresponding protein was normal, but the shedding of the Fasligand was impaired in T-cells. Additionally, analyzing Epstein-Barr virus (EBV)-transformed B-cells, our results indicate impaired AICD in ALPS-FASLG patients. CONCLUSION:Patients with autosomal recessive inheritance of ALPS-FASLG have a severe phenotype and a partial defect in AICD in T- and B-cell lines. The Fasligand could play a key role in immune surveillance preventing malignancy. 10.1038/pr.2015.170
    RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease. Mao Huawei,Yang Wanling,Latour Sylvain,Yang Jing,Winter Sarah,Zheng Jian,Ni Ke,Lv Minmin,Liu Chenjing,Huang Hongmei,Chan Koon-Wing,Pui-Wah Lee Pamela,Tu Wenwei,Fischer Alain,Lau Yu-Lung The Journal of allergy and clinical immunology BACKGROUND:Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to impaired apoptosis. It was initially regarded as a very rare disease, but recent studies show that it may be more common than previously thought. Defects in a couple of genes have been identified in a proportion of patients with ALPS, but around one-third of such patients remain undefined genetically. OBJECTIVE:We describe 2 siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype. METHODS:Whole-exome sequencing and molecular and functional analyses were used to identify and characterize the genetic defect. Clinical and immunological analysis was also performed and reported. RESULTS:The 2 patients presented with chronic lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, immune thrombocytopenia, and the presence of antinuclear autoantibody and other autoantibodies, but normal double-negative T cells. They also suffered from recurrent infections. Novel compound heterozygous mutations of RASGRP1 encoding Ras guanyl nucleotide releasing protein 1 were identified in the 2 siblings. The mutations impaired T-cell receptor signaling, leading to defective T-cell activation and proliferation, as well as impaired activation-induced cell death of T cells. CONCLUSIONS:This study shows for the first time that RASGRP1 mutation should be considered in patients with ALPS-like disease. We also propose to investigate the intracellular proteins involved in the T-cell receptor signaling pathway in similar patients but with unknown genetic cause. 10.1016/j.jaci.2017.10.026
    Paradoxical CD4 Lymphopenia in Autoimmune Lymphoproliferative Syndrome (ALPS). Lisco Andrea,Wong Chun-Shu,Price Susan,Ye Peiying,Niemela Julie,Anderson Megan,Richards Elizabeth,Manion Maura,Mystakelis Harry,Similuk Morgan,Lo Bernice,Stoddard Jennifer,Rosenzweig Sergio,Vanpouille Christophe,Rupert Adam,Maric Irina,Perez-Diez Ainhoa,Parenti David,Burbelo Peter D,Rao V Koneti,Sereti Irini Frontiers in immunology Autoimmune lymphoproliferative syndrome (ALPS) is caused by germline or somatic loss of function mutations resulting in impaired apoptosis and consequent expansion of T-lymphocytes causing organomegaly and autoimmune anemia, neutropenia and thrombocytopenia. Herein, we report on a case of disseminated varicella zoster infection after post-partum vaccination in a patient found to have CD4 lymphopenia and eventually diagnosed with ALPS caused by a novel germline missense mutation in death-domain. A subsequent retrospective analysis of 169 patients of the NIH ALPS-FAS cohort, revealed that CD4-T-cells lymphopenia (< 300 cells/μl) may occur in 5% of ALPS-FAS patients irrespectively of the underlying genetic defect, organomegaly or immunosuppressive treatment. Although immunophenotyping did not show depletion of specific CD4-T-cells subpopulations, CD4-lymphopenic ALPS-FAS subjects had an expansion of a subset of circulating T-follicular-helper (cTfh) cells, associated with autoantibody production (CCR7PD-1). Furthermore, autoantibodies binding on CD4-T-cells were detected in 50% of the CD4-lymphopenic ALPS-FAS patients and caused cytotoxicity in a natural killer (NK)-mediated antibody-dependent-cellular cytotoxicity assay. Such autoantibodies can therefore be associated with CD4-T-cell death, impaired activation induced proliferation or impaired trafficking. The expansion of autoreactive T-cells in ALPS-FAS is known to be associated with autoimmune clinical manifestations, however our study reveals that ALPS-FAS can also be associated with a paradoxical depletion of CD4-T-cells due to the presence of autoantibodies on the surface of CD4-T-cells which can in turn result in increased susceptibility to opportunistic infections. These novel findings have implications for the diagnosis, clinical monitoring, and management of patients with ALPS-FAS. 10.3389/fimmu.2019.01193
    Autoimmune Lymphoproliferative Syndrome Masquerading as Posttransplant Lymphoproliferative Disorder. Jeffreys Sarah M,Levy Rebecca A,Crary Shelley E Journal of pediatric hematology/oncology We present a case of a 2-year-old female presenting with diffuse lymphadenopathy 2 years following orthotopic heart transplant. Initially, she was diagnosed with posttransplant lymphoproliferative disease based on clinical presentation and pathology and she was treated accordingly. Because of persistent lymphadenopathy following the completion of chemotherapy and new onset of autoimmune cytopenias, repeat flow of the lymph node showed an elevated double negative T-cell population prompting evaluation for autoimmune lymphoproliferative syndrome (ALPS). A complete workup was confirmative of a germline Fas mutation consistent with ALPS-FAS. This case emphasizes the importance of considering ALPS-FAS in a patient with lymphadenopathy of unknown cause. 10.1097/MPH.0000000000000981
    Synergistic defects of novo FAS and homozygous UNC13D leading to autoimmune lymphoproliferative syndrome-like disease: A 10-year-old Chinese boy case report. Gu Hao,Ma Jie,Chen Zhenping,Wang Jing,Zhang Rui,Wu Runhui Gene Autoimmune lymphoproliferative syndrome (ALPS) usually presents in childhood with fever, nonmalignant splenomegaly and lymphadenopathy along with hemocytopenia. This case report describes a 10-year-old boy presenting with signs of autoimmune disease, splenomegaly, hepatomegaly and resistant hemocytopenia. Sirolimus controlled the relapsed thrombocytopenia after splenectomy. Sequencing of the FAS gene identified two spontaneous heterozygous mutations (c.234 T > G, p.D78E) (c.236dupA, p.P80Tfs*26). The boy's homozygous missense variation (c.2588G > A, p.G863D) (rs140184929) in UNC13D gene had been identified as being related to familial hemophagocytic lymphohistiocytosis (FHL). TCRαβ + CD4/CD8 double-negative T cells (markers of ALPS) were not significantly increased from the outset. Elevated cytokines, such as interferon (IFN)-γ, interleukin (IL)-6 and tumor necrosis factor α decreased to normal levels after splenectomy whereas IL-10 remained high. Immunological analysis of the patient revealed a marked depletion of forkhead-box P3 expressing regulatory T cells (Treg) and Th17 cells. The obtained data demonstrate that mutations to FAS and UNC13D which result in overwhelming T-cell and macrophage activation, one associated with inhibited Treg cell development and a severe ALPS-like symptom. Therefore, we propose that variations of UND13D may be a risk factor of ALPS development. 10.1016/j.gene.2018.05.097
    Updated Understanding of Autoimmune Lymphoproliferative Syndrome (ALPS). Li Pu,Huang Ping,Yang Ye,Hao Mu,Peng Hongwei,Li Fei Clinical reviews in allergy & immunology Autoimmune lymphoproliferative syndrome (ALPS), a disorder characterized by immune dysregulation due to disrupted lymphocyte homeostasis, is mainly resulted from the mutations in FAS-mediated apoptotic pathway. In addition, other mutations of the genes such as Fas-ligand (FASLG), Caspase 10 (CASP10) and Caspase 8 (CASP8), NRAS and KRAS have also been observed in a small number of patients with ALPS or ALPS-related disorders. However, approximately 20-30% of patients with ALPS have unidentified defect. Its clinical manifestations observed in multiple family members include unexplained lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias such as thrombocytopenia, neutropenia, and anemia due to excessive production of antibodies by lymphocytes, elevated number of double-negative T (DNT) cells, and increased risk of lymphoma. As a very rare disease, ALPS was first characterized in the early 1990s. More than 300 families with hereditary ALPS have been reported till now; nearly 500 patients from these families have been studied and followed worldwide over the last 20 years. ALPS has historically considered as a primary immune defect presenting in early childhood, however, recent studies have shown that it may be more common than previous thought because adult onset presentation is increasingly becoming recognized and more adult ALPS patients are diagnosed. The new genetic and biological insights have improved the understanding of ALPS and a number of targeted therapeutic strategies such as mycophenolate mofetil, sirolimus, and pentostatin have been successfully applied in ALPS patients with promising treatment efficacy. This article comprehensively reviews the clinical and laboratory manifestations, new research advances in the molecular pathogenesis, diagnosis and treatments of this disorder. 10.1007/s12016-015-8466-y
    Autoimmune Lymphoproliferative Syndrome: An Overview. Matson Daniel R,Yang David T Archives of pathology & laboratory medicine Autoimmune lymphoproliferative syndrome (ALPS) is an inherited nonmalignant lymphoproliferative disorder characterized by heterozygous mutations within the first apoptosis signal receptor (FAS) signaling pathway. Defects in FAS-mediated apoptosis cause an expansion and accumulation of autoreactive CD4 and CD8 (double-negative) T cells, leading to cytopenias, splenomegaly, lymphadenopathy, autoimmune disorders, and a greatly increased lifetime risk of lymphoma. The differential diagnosis of ALPS includes infection, other inherited immunodeficiency disorders, primary and secondary autoimmune syndromes, and lymphoma. The most consistent pathologic feature is a florid paracortical expansion of double-negative T cells in lymph nodes. A presumptive clinical diagnosis can be made from symptoms and a constellation of laboratory test results. However, a definitive diagnosis requires ancillary testing and enables disease subclassification. Recognition of ALPS is critical, as treatment with immunosuppressive therapies can effectively reduce or ameliorate symptoms for most patients. 10.5858/arpa.2018-0190-RS
    Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease. Nabhani Schafiq,Ginzel Sebastian,Miskin Hagit,Revel-Vilk Shoshana,Harlev Dan,Fleckenstein Bernhard,Hönscheid Andrea,Oommen Prasad T,Kuhlen Michaela,Thiele Ralf,Laws Hans-Jürgen,Borkhardt Arndt,Stepensky Polina,Fischer Ute Haematologica Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20-30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease. 10.3324/haematol.2014.114967