CTLA-4 haploinsufficiency in a patient with an autoimmune lymphoproliferative disorder.
Ontology highlight
ABSTRACT:
SUBMITTER: Kucuk ZY
PROVIDER: S-EPMC5591763 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
Publications
CTLA-4 haploinsufficiency in a patient with an autoimmune lymphoproliferative disorder.
Kucuk Zeynep Yesim ZY Charbonnier Louis-Marie LM McMasters Richard L RL Chatila Talal T Bleesing Jack J JJ
The Journal of allergy and clinical immunology 20170330 3
Similar Datasets
Project description: Not available
| S-EPMC5889970 | biostudies-literature
Project description: Not available
| S-EPMC10927476 | biostudies-literature
Project description:The autoimmune lymphoproliferative syndrome (ALPS) is characterized by early-onset lymphadenopathy, splenomegaly, immune cytopenias, and an increased risk for B cell lymphomas. Most ALPS patients harbor mutations in the FAS gene, which regulates lymphocyte apoptosis. These are commonly missense mutations affecting the intracellular region of the protein and have a dominant-negative effect on the signaling pathway. However, analysis of a large cohort of ALPS patients revealed that ∼30% have mutations affecting the extracellular region of FAS, and among these, 70% are nonsense, splice site, or insertions/deletions with frameshift for which no dominant-negative effect would be expected. We evaluated the latter patients to understand the mechanism(s) by which these mutations disrupted the FAS pathway and resulted in clinical disease. We demonstrated that most extracellular-region FAS mutations induce low FAS expression due to nonsense-mediated RNA decay or protein instability, resulting in defective death-inducing signaling complex formation and impaired apoptosis, although to a lesser extent as compared with intracellular mutations. The apoptosis defect could be corrected by FAS overexpression in vitro. Our findings define haploinsufficiency as a common disease mechanism in ALPS patients with extracellular FAS mutations.
| S-EPMC3725553 | biostudies-literature
Project description:In this study we focussed on malignant post-transplant lymphomas. Post-transplant lymphoma is strongly associated with Epstein-Barr Virus (EBV) infection in contrast to lymphoma arising in an immunocompetent population. Nevertheless, about 1 in 3 PTLD cases are negative for EBV. We used a microarray to define the gene expression profile of different PTLDs to elucidate the pathogenesis of EBV(+) and EBV(-) PTLD and to define whether EBV(-) PTLD is biologically different from EBV(-) lymphoma arising in an immunocompetent host. PTLD patient samples were randomly selected for RNA extraction and hybridization on an Affymetrix platform. The post-transplant tumors consisted of homogenous sheets of neoplastic cells ensuring reliability of the gene expression data.
2012-06-22 | E-GEOD-38885 | biostudies-arrayexpress
Project description:Other iatrogenic immunodeficiency lymphoproliferative disorders (oii-LPD) are defined as lymphoid proliferations or lymphomas that occur in patients taking immunosuppressive agents (ISA) for autoimmune disorders (AID). Although methotrexate and tumor necrosis factor-alpha inhibitors cause oii-LPD, the association between corticosteroids and lymphomagenesis remains unknown. Herein, we present the case of a 51-year-old woman with oii-LPD caused by corticosteroid use for autoimmune hemolytic anemia (AIHA). The diagnosis of AIHA was made in May 2016, and AIHA had been well-controlled for 5 years with oral prednisolone (PSL). During a regular follow-up visit in March 2022, an abnormal increase in atypical lymphoid cells in the peripheral blood was found. The bone marrow biopsy specimens showed local aggregations of large cells that were identified as lymphoplasmacytic cells and plasma cells, and that were positive for cluster of differentiation (CD)19 and CD20, with apparent nucleoli among the diffuse infiltration of atypical small lymphocytes. The large cells were partially positive for the Epstein-Barr encoding region in situ hybridization and latent membrane protein 1, which confirmed Epstein-Barr virus (EBV)-affected lymphomagenesis. To our knowledge, this is the first report of an oii-LPD case shown to be induced by corticosteroid use for AID.
| S-EPMC9761222 | biostudies-literature
Project description:In this study we focussed on malignant post-transplant lymphomas. Post-transplant lymphoma is strongly associated with Epstein-Barr Virus (EBV) infection in contrast to lymphoma arising in an immunocompetent population. Nevertheless, about 1 in 3 PTLD cases are negative for EBV. We used a microarray to define the gene expression profile of different PTLDs to elucidate the pathogenesis of EBV(+) and EBV(-) PTLD and to define whether EBV(-) PTLD is biologically different from EBV(-) lymphoma arising in an immunocompetent host.
2012-06-23 | GSE38885 | GEO
Project description:Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.
| S-EPMC1895548 | biostudies-literature
Project description:Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis, permitting accumulation of lymphoid mass and persistence of autoreactive cells that often manifest in childhood with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and recurring multilineage cytopenias. Cytopenias in these patients can be the result of splenic sequestration as well as autoimmune complications manifesting as autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia. More than 300 families with hereditary ALPS have now been described; nearly 500 patients from these families have been studied and followed worldwide over the last 20 years by our colleagues and ourselves. Some of these patients with FAS mutations affecting the intracellular portion of the FAS protein also have an increased risk of B-cell lymphoma. The best approaches to diagnosis, follow-up, and management of ALPS, its associated cytopenias, and other complications resulting from infiltrative lymphoproliferation and autoimmunity are presented.
| S-EPMC3228494 | biostudies-literature
Project description:Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (CTLA4) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the β-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (Treg) differentiation from naïve αβ and γδ T cells, even in the absence of transforming growth factor-β. Consistent with DECTIN-1's Treg-boosting ability, partial DECTIN-1 deficiency exacerbated the Treg defect conferred by CTL4-4h. DECTIN-1/CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.
| S-EPMC10699772 | biostudies-literature
Project description:RationalePatients with autoimmune lymphoproliferative syndrome (ALPS), a disorder of impaired lymphocyte apoptosis, often undergo radiographic chest imaging to evaluate the presence and progression of lymphadenopathy. These images often lead to parenchymal and interstitial lung findings of unclear clinical significance.ObjectivesTo characterize the pulmonary findings associated with ALPS and to determine if lung abnormalities present on computed tomographic (CT) imaging of the chest correlate with infection or functional status.MethodsPatients with lung abnormalities observed on chest CT scans were retrospectively identified from the largest known ALPS cohort. Lung computed tomography findings were characterized and correlated with medical records, bronchoalveolar lavage, biopsy, and lung function.Measurements and main resultsCT images of the chest were available for 234 (92%) of 255 of the patients with ALPS. Among patients with a chest CT scan, 18 (8%) had lung abnormalities on at least one CT scan. Fourteen (78%) of those 18 were classified as having ALPS with undetermined genetic defect. Most patients (n = 16 [89%]) with lung lesions were asymptomatic. However, two (11%) of them had associated dyspnea and/or desaturation on room air. Immunosuppressive treatment was administered for lung disease in nine (50%) cases, and all were followed for clinical outcomes.ConclusionsPatients with ALPS can develop chest radiographic findings with protean manifestations that may mimic pulmonary infection. Management of patients with ALPS with incidental lung lesions identified by CT imaging should be guided by clinical correlation. Symptomatic patients may benefit from chest CT imaging and lesion biopsy to exclude infection and guide administration of immunosuppressive therapy.
| S-EPMC5021079 | biostudies-literature