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V. Koneti Rao - One of the best experts on this subject based on the ideXlab platform.
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Bone marrow findings in Autoimmune Lymphoproliferative Syndrome with germline FAS mutation.
Haematologica, 2016Co-Authors: Yi Xie, V. Koneti Rao, Stefania Pittaluga, Susan Price, Mark Raffeld, Jamie Hahn, Elaine S. Jaffe, Irina MaricAbstract:Autoimmune Lymphoproliferative Syndrome is a rare genetic disorder characterized by defective FAS-mediated apoptosis, Autoimmune disease, accumulation of mature T-cell receptor alpha/beta positive, CD4 and CD8 double-negative T cells and increased risk of lymphoma. Despite frequent hematologic abnormalities, literature is scarce regarding the bone marrow pathology in Autoimmune Lymphoproliferative Syndrome. We retrospectively reviewed 3l bone marrow biopsies from a cohort of 240 patients with germline FAS mutations. All biopsies were performed for the evaluation of cytopenias or to rule out lymphoma. Clinical information was collected and morphological, immunohistochemical, flow cytometric and molecular studies were performed. Bone marrow lymphocytosis was the predominant feature, present in 74% (23/31) of biopsies. The lymphoid cells showed several different patterns of infiltration, most often forming aggregates comprising T cells in 15 cases, B cells in one and a mixture of T and B cells in the other seven cases. Double-negative T cells were detected by immunohistochemistry in the minority of cases (10/31; 32%); significantly, all but one of these cases had prominent double-negative T-lymphoid aggregates, which in four cases diffusely replaced the marrow space. One case showed features of Rosai-Dorfman disease, containing scattered S-100+ cells with emperipolesis and double-negative T cells. No clonal B or T cells were detected by polymerase chain reaction in any evaluated cases. Classical Hodgkin lymphoma was identified in three cases. Our results demonstrate that infiltrates of T cells, or rarely B cells, can be extensive in patients with Autoimmune Lymphoproliferative Syndrome, mimicking lymphoma. A multi-modality approach, integrating clinical, histological, immunohistochemical as well as other ancillary tests, can help avoid this diagnostic pitfall. This study is registered at Clinicaltrials.gov ID # NCT00001350
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Ocular Inflammatory Disorders in Autoimmune Lymphoproliferative Syndrome (ALPS).
Ocular immunology and inflammation, 2016Co-Authors: Didar Ucar, V. Koneti Rao, Robert B. Nussenblatt, Jane S. Kim, Rachel J. Bishop, H. Nida SenAbstract:ABSTRACTPurpose: To describe inflammatory ocular findings in patients with Autoimmune Lymphoproliferative Syndrome (ALPS).Methods: A retrospective review of medical records for ALPS patients seen at the National Eye Institute between 2003 and 2013.Results: A total of 29 ALPS patients previously referred for ocular or visual symptoms or with a history of prolonged corticosteroid use, were identified. Mean age was 20 years (range: 4–66 years). The majority were male (n = 21, 72.4%) and Caucasian (n = 24, 82.8%). Ten (34.5%) had abnormal ocular findings, the most common of which was an ocular inflammatory disorder (n = 4, 13.8%). Uveitis was seen in two patients with ALPS-FAS and one with ALPS-U, all of whom required long-term systemic immunosuppression. One patient with ALPS-FAS had a history of optic neuritis.Conclusions: ALPS can have intraocular inflammatory manifestations that require routine follow-up to ensure appropriate and timely treatment of intraocular disease. Long-term immunosuppression may be ...
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Autoimmune Lymphoproliferative Syndrome: an Update and Review of the Literature
Current Allergy and Asthma Reports, 2014Co-Authors: Shaili Shah, V. Koneti Rao, Teresa K. TarrantAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is characterized by immune dysregulation due to a defect in lymphocyte apoptosis. The clinical manifestations may be noted in multiple family members and include lymphadenopathy, splenomegaly, increased risk of lymphoma, and Autoimmune disease, which typically involves hematopoietic cell lines manifesting as multilineage cytopenias. Since the disease was first characterized in the early 1990s, there have been many advances in the diagnosis and management of this Syndrome. The inherited genetic defect of many ALPS patients has involved (FAS) pathway signaling proteins, but there remain those patients who carry undefined genetic defects. Despite ALPS having historically been considered a primary immune defect presenting in early childhood, adult onset presentation is increasingly becoming recognized and more so in genetically undefined patients and those with somatic FAS mutations. Thus, future research may identify novel pathways and/or regulatory proteins important in lymphocyte activation and apoptosis.
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Autoimmune Lymphoproliferative Syndrome Misdiagnosed as Hemophagocytic Lymphohistiocytosis
Pediatrics, 2013Co-Authors: Amanda Rudman Spergel, Julie E. Niemela, Thomas A. Fleisher, Susan Price, Kelly Walkovich, Dowain A. Wright, V. Koneti RaoAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare inherited disorder of apoptosis, most commonly due to mutations in the FAS (TNFRSF6) gene. It presents with chronic lymphadenopathy, splenomegaly, and symptomatic multilineage cytopenias in an otherwise healthy child. Unfortunately, these clinical findings are also noted in other childhood Lymphoproliferative conditions, such as leukemia, lymphoma, and hemophagocytic lymphohistiocytosis, which can confound the diagnosis. This report describes a 6-year-old girl with symptoms misdiagnosed as hemophagocytic lymphohistiocytosis and treated with chemotherapy before the recognition that her symptoms and laboratory values were consistent with a somatic FAS mutation leading to ALPS. This case should alert pediatricians to include ALPS in the differential diagnosis of a child with lymphadenopathy, splenomegaly, and cytopenias; obtain discriminating screening laboratory biomarkers, such as serum vitamin B-12 and ferritin levels; and, in the setting of a highly suspicious clinical scenario for ALPS, pursue testing for somatic FAS mutations when germ-line mutation testing is negative.
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Elevated vitamin B12 levels in Autoimmune Lymphoproliferative Syndrome attributable to elevated haptocorrin in lymphocytes
Clinical biochemistry, 2012Co-Authors: Raffick A.r. Bowen, Janet K Dale, Kennichi C. Dowdell, Steven K. Drake, Thomas A. Fleisher, Glen L. Hortin, Alan T. Remaley, Ebba Nexo, V. Koneti RaoAbstract:Objective Identify the etiology of elevated B12 in Autoimmune Lymphoproliferative Syndrome (ALPS).
Sharon E. Straus - One of the best experts on this subject based on the ideXlab platform.
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Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with Autoimmune Lymphoproliferative Syndrome.
British journal of haematology, 2005Co-Authors: V. Koneti Rao, Jennifer M Puck, Janet K Dale, Joie Davis, Thomas A. Fleisher, Faith Dugan, Jean Tretler, John K. Hurley, Sharon E. StrausAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of apoptosis associated most often with heritable FAS mutations leading to lymphadenopathy, hypersplenism and chronic refractory Autoimmune cytopenias. Mycophenolate mofetil (MMF) was used to treat cytopenias in 13 ALPS patients aged 9 months to 17 years from a cohort of 118 children (aged < 18 years) and 82 adults. Twelve responded for a median follow-up of 49 weeks (range 38-240 weeks), defined by maintenance of adequate blood counts and reduction in dosage or cessation of other immunosuppressive agents. This preliminary experience suggests that MMF may spare steroid usage in patients with ALPS-associated cytopenias.
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Bilateral uveitis in a patient with Autoimmune Lymphoproliferative Syndrome
American journal of ophthalmology, 2005Co-Authors: Wee Kiak Lim, Sharon E. Straus, R. Ursea, Koneti Rao, Ronald Buggage, Eric B. Suhler, Faith Dugan, Chi-chao Chan, Robert B. NussenblattAbstract:Purpose We report a case of Autoimmune Lymphoproliferative Syndrome (ALPS) presenting with bilateral uveitis. Design Observational case report. Methods Review of case record, serum and aqueous IL-10 and IL-6 cytokine results, and immunosuppressive treatment of a patient with a mutation in the gene encoding Fas. Results Control of the intermediate uveitis required sustained doses of topical and periocular corticosteroids as well as systemic cyclosporine. The serum IL-10 level was elevated, as commonly seen in ALPS, but the aqueous IL-10 was not. Conclusions Despite a Th2 immune predominance in ALPS, uveitis, a Th1-mediated disease, may still manifest in these patients. The pathogenesis of uveitis in ALPS may differ from that of the systemic disease overall. Long-term follow-up is required for patients with uveitis associated with ALPS.
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Autoimmune Lymphoproliferative Syndrome.
Current opinion in rheumatology, 2003Co-Authors: Michael C. Sneller, Janet K Dale, Sharon E. StrausAbstract:Autoimmune Lymphoproliferative Syndrome arises early in childhood in people who inherit mutations in genes that mediate lymphocyte apoptosis, or programed cell death. In the immune system, antigen-induced lymphocyte apoptosis maintains immune homeostasis by limiting lymphocyte accumulation and minim
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aberrant t cell antigen receptor mediated responses in Autoimmune Lymphoproliferative Syndrome
Clinical Immunology, 2002Co-Authors: Frederick D Goldman, Jennifer M Puck, Sharon E. Straus, Rajeev Vibhakar, Zuhair K Ballas, Clay Hollenback, Thomas W Loew, Anthony Thompson, Kejing Song, Robert T CookAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of defective lymphocyte apoptosis due to mutations of the Fas receptor and other molecules in the Fas signaling pathway. In addition to accumulation of CD4(-) CD8(-) double-negative (DN) T cells, many patients display a dysregulated cytokine pattern with dysfunctional T cells, suggesting Fas defects may impact pathways of T-cell activation/differentiation. Here, we report two novel mutations in the Fas receptor resulting in an ALPS phenotype. Utilizing flow cytometry, we found anti-CD3 activated CD4(+) T cells from these patients were incapable of fully upregulating activation markers (CD25, CD69, and CD40L) or producing interferon-gamma and IL-2. Additionally, DN T cells were unable to transduce proximal T-cell antigen receptor signals or produce cytokines. Furthermore, DN T cells overexpressed CD57 and phenotypically resembled end-stage effector cells. As DN T cells were essentially anergic, the clinical manifestations of autoimmunity are more likely to be a consequence of aberrant cytokine secretion within the CD4(+) T-cell subpopulation.
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RBC autoantibodies in Autoimmune Lymphoproliferative Syndrome.
Transfusion, 2001Co-Authors: David F. Stroncek, Janet K Dale, Laura B. Carter, Jo L. Procter, Sharon E. StrausAbstract:BACKGROUND: Patients with Autoimmune Lymphoproliferative Syndrome (ALPS) have an autosomal dominant genetic defect that affects lymphocyte apoptosis and is associated with chronic nonmalignant lymphadenopathy, splenomegaly, and autoimmunity, particularly affecting RBCs, WBCs, and platelets. STUDY DESIGN AND METHODS: DATs were performed on 34 consecutive patients with ALPS and 37 of their clinically unaffected relatives. The effects of age, sex, race, and immunoglobulin levels on the incidence of autoantibodies and clinical hemolysis were assessed. RESULTS: The DAT was positive in 21 (62%) of ALPS patients but in only 1 (3%) of their relatives (p = 0.001). The DAT reacted because of IgG alone in 43 percent, complement alone in 5 percent, and IgG plus complement in 19 percent; 33 percent of the patients′ cells had a positive reaction with polyspecific reagent only. All 10 ALPS patients with a history of hemolytic anemia had a positive DAT. Sixty percent of them had only IgG on their cells, 30 percent had IgG and complement, and 10 percent reacted only with polyspecific reagent. Of the 11 patients with a positive DAT and no history of hemolytic anemia, IgG alone was present in 27 percent, complement alone in 9%, and IgG plus complement in 9 percent; 55 percent had positive DATs only with polyspecific reagent. Among ALPS patients, those with a positive DAT had greater quantities of cells with increased α and β T-cell receptors that phenotyped as CD4–CD8– and higher IgG levels. CONCLUSIONS: The DAT results in ALPS patients are most similar to those found in warm Autoimmune hemolytic anemia. The DAT is useful to distinguish affected and unaffected persons within an ALPS family.
Thomas A. Fleisher - One of the best experts on this subject based on the ideXlab platform.
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Autoimmune Lymphoproliferative Syndrome Misdiagnosed as Hemophagocytic Lymphohistiocytosis
Pediatrics, 2013Co-Authors: Amanda Rudman Spergel, Julie E. Niemela, Thomas A. Fleisher, Susan Price, Kelly Walkovich, Dowain A. Wright, V. Koneti RaoAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare inherited disorder of apoptosis, most commonly due to mutations in the FAS (TNFRSF6) gene. It presents with chronic lymphadenopathy, splenomegaly, and symptomatic multilineage cytopenias in an otherwise healthy child. Unfortunately, these clinical findings are also noted in other childhood Lymphoproliferative conditions, such as leukemia, lymphoma, and hemophagocytic lymphohistiocytosis, which can confound the diagnosis. This report describes a 6-year-old girl with symptoms misdiagnosed as hemophagocytic lymphohistiocytosis and treated with chemotherapy before the recognition that her symptoms and laboratory values were consistent with a somatic FAS mutation leading to ALPS. This case should alert pediatricians to include ALPS in the differential diagnosis of a child with lymphadenopathy, splenomegaly, and cytopenias; obtain discriminating screening laboratory biomarkers, such as serum vitamin B-12 and ferritin levels; and, in the setting of a highly suspicious clinical scenario for ALPS, pursue testing for somatic FAS mutations when germ-line mutation testing is negative.
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Elevated vitamin B12 levels in Autoimmune Lymphoproliferative Syndrome attributable to elevated haptocorrin in lymphocytes
Clinical biochemistry, 2012Co-Authors: Raffick A.r. Bowen, Janet K Dale, Kennichi C. Dowdell, Steven K. Drake, Thomas A. Fleisher, Glen L. Hortin, Alan T. Remaley, Ebba Nexo, V. Koneti RaoAbstract:Objective Identify the etiology of elevated B12 in Autoimmune Lymphoproliferative Syndrome (ALPS).
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Fluorodeoxyglucose positron emission tomography (FDG-PET) for monitoring lymphadenopathy in the Autoimmune Lymphoproliferative Syndrome (ALPS).
American journal of hematology, 2006Co-Authors: V. Koneti Rao, Jennifer M Puck, Janet K Dale, Thomas A. Fleisher, Faith Dugan, Jorge A. Carrasquillo, Stephen L. Bacharach, Millie Whatley, Jean Tretler, Wyndham H. WilsonAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is associated with mutations that impair the activity of lymphocyte apoptosis proteins, leading to chronic lymphadenopathy, hepatosplenomegaly, autoimmunity, and an increased risk of lymphoma. We investigated the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) in discriminating benign from malignant lymphadenopathy in ALPS. We report that FDG avidity of benign lymph nodes in ALPS can be high and, hence, by itself does not imply presence of lymphoma; but FDG-PET can help guide the decision for selecting which of many enlarged nodes in ALPS patients to biopsy when lymphoma is suspected.
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Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with Autoimmune Lymphoproliferative Syndrome.
British journal of haematology, 2005Co-Authors: V. Koneti Rao, Jennifer M Puck, Janet K Dale, Joie Davis, Thomas A. Fleisher, Faith Dugan, Jean Tretler, John K. Hurley, Sharon E. StrausAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of apoptosis associated most often with heritable FAS mutations leading to lymphadenopathy, hypersplenism and chronic refractory Autoimmune cytopenias. Mycophenolate mofetil (MMF) was used to treat cytopenias in 13 ALPS patients aged 9 months to 17 years from a cohort of 118 children (aged < 18 years) and 82 adults. Twelve responded for a median follow-up of 49 weeks (range 38-240 weeks), defined by maintenance of adequate blood counts and reduction in dosage or cessation of other immunosuppressive agents. This preliminary experience suggests that MMF may spare steroid usage in patients with ALPS-associated cytopenias.
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Autoimmune Lymphoproliferative Syndrome
Current Opinion in Allergy and Clinical Immunology, 2004Co-Authors: Joao Bosco Oliveira, Thomas A. FleisherAbstract:December 2005The Autoimmune Lymphoproliferative Syndrome is a recently described human disorder that affects lymphocyte programmed cell death (apoptosis), resulting in altered immune homeo-stasis. The hallmark feature of this human “experiment of nature” is lymphoproliferation, presenting as non-malignant lymphadenopathy and splenomegaly during childhood [1–3]. This is often accompanied by the development of autoimmunity that primarily affects blood cells. Laboratory findingsincludean expansion of a normally rare lymphoid subpopulation of T cells that do not express CD4 or CD8 (double negative T cells) but express the alpha/beta form of the T cell antigen receptor [Figure 1] [4]. In addition, ALPS patients often have polyclonal increases in serum immunoglobulin levels as well as increased serum interleukin-10 levels [5]. The clinical course typically in-volves unexplained and persistent lymphadenopathy presenting early in childhood followed by the appearance of Autoimmune disease, most frequently Autoimmune hemolytic anemia and/or Autoimmune thrombocytopenia. Immune neutropenia may also be seen, while other Autoimmune disorders present only infre-quently. Autoimmunity can occur throughout life although the initial presentation is most common during childhood. While conventional therapy has been the mainstay for managing the immune cytopenias, newer treatment approaches have been used as a splenectomy-sparing alternative due to the infectious risk that follows this surgical procedure [6]. Lymphoid malig-nancy is also more common in ALPS and can appear at any age but is most frequent during adulthood. The clinical evolution of ALPS from initial presentation varies, although not infrequently the lymphadenopathy becomes less prominent following adoles-cence. Patients require regular monitoring due to the lifetime risk of lymphoma development. The clinical and laboratory observations in these patients have been complemented by a series of studies documenting the underlying molecular defect in the majority of ALPS patients.The initial focus on in vitro Fas-mediated lymphocyte apop-tosis in ALPS was prompted by published studies definingthe underlying defects in the lpr and gld murine models of autoimmunity [8]. These reports identifiedautosomalreces-sive mutations in either the gene encoding Fas (lpr) or Fas ligand (gld), both of which resulted in defective Fas-mediated lymphocyte apoptosis [7]. It had also been observed that the severity of disease was dependent on the genetic background of the mice expressing either mutation, suggesting that ad-ditional factors impact disease penetrance. Importantly, the hallmark findingsinthelpr and gld mice include an increase in alpha/beta DNT cells associated with massive, non-malig-nant lymphadenopathy and an increased risk of developing a B cell lineage tumor (plasmacytoma) as well as systemic lu-pus erythematosus-like autoimmunity. Recognition that these two murine models had many similarities with the clinical picture in ALPS prompted evaluation of the Fas-mediated death pathway in the patients. These studies noted that the human disorder was associated with defective in vitro Fas-mediated lymphocyte apoptosis in both activated T cells and Epstein-Barr virus-transformed B cell lines. These findings,when linked to the mutation data in the lpr and gld mice, prompted the evaluation of the genes encoding Fas and Fas
Jennifer M Puck - One of the best experts on this subject based on the ideXlab platform.
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Autoimmune Lymphoproliferative Syndrome due to FAS mutations outside the signal-transducing death domain: molecular mechanisms and clinical penetrance
Genetics in medicine : official journal of the American College of Medical Genetics, 2011Co-Authors: Amy P. Hsu, Kennichi C. Dowdell, Joie Davis, Julie E. Niemela, Stacie M. Anderson, Pamela A. Shaw, V. Koneti Rao, Jennifer M PuckAbstract:Autoimmune Lymphoproliferative Syndrome is a disorder of lymphocyte apoptosis. Although FAS molecules bearing mutations in the signal-transducing intracellular death domain exhibit dominant-negative interference with FAS-mediated apoptosis, mechanisms for pathology of non-death domain FAS mutations causing Autoimmune Lymphoproliferative Syndrome are poorly defined. RNA stability, protein expression, ligand binding, and ability to transmit apoptosis signals by anti-FAS antibody or FAS ligand were determined for a cohort of 39 patients with non-death domain Autoimmune Lymphoproliferative Syndrome. Correlations between mutation type and disease penetrance were established in mutation-positive family members. Frameshifts or transcriptional stop mutations before exon 7 resulted in messenger RNA haploinsufficiency, whereas an amino-terminal signal sequence mutation and certain intracellular truncations prevented cell surface localization of FAS. All resulted in decreased FAS localization, inability to bind FAS ligand, and reduced FAS ligand-induced apoptosis. Extracellular missense mutations and in-frame deletions expressed defective FAS protein, failed to bind FAS ligand, and exhibited dominant-negative interference with FAS-mediated apoptosis. Mutation-positive relatives with haploinsufficient or extracellular mutations had lower penetrance of Autoimmune Lymphoproliferative Syndrome clinical phenotypes than did relatives with death domain mutations. We have defined molecular mechanisms by which non-death domain FAS mutations result in reduced lymphocyte apoptosis, established a hierarchy of genotype-phenotype correlation among mutation-positive relatives of patients with Autoimmune Lymphoproliferative Syndrome, and demonstrated that FAS haploinsufficiency can lead to Autoimmune Lymphoproliferative Syndrome. Genet Med 2012:14(1):81–89
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nras mutation causes a human Autoimmune Lymphoproliferative Syndrome
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Joao Bosco Oliveira, Julie E. Niemela, Nicolas Bidere, Lixin Zheng, Keiko Sakai, Cynthia P Nix, Robert L Danner, Jennifer Barb, Peter J Munson, Jennifer M PuckAbstract:The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization, and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous, and Costello Syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune Lymphoproliferative Syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4−, CD8− αβ T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving TNF receptor superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling, which markedly decreases the proapoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyltransferase inhibitors should be examined in human Autoimmune and lymphocyte homeostasis disorders.
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Fluorodeoxyglucose positron emission tomography (FDG-PET) for monitoring lymphadenopathy in the Autoimmune Lymphoproliferative Syndrome (ALPS).
American journal of hematology, 2006Co-Authors: V. Koneti Rao, Jennifer M Puck, Janet K Dale, Thomas A. Fleisher, Faith Dugan, Jorge A. Carrasquillo, Stephen L. Bacharach, Millie Whatley, Jean Tretler, Wyndham H. WilsonAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is associated with mutations that impair the activity of lymphocyte apoptosis proteins, leading to chronic lymphadenopathy, hepatosplenomegaly, autoimmunity, and an increased risk of lymphoma. We investigated the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) in discriminating benign from malignant lymphadenopathy in ALPS. We report that FDG avidity of benign lymph nodes in ALPS can be high and, hence, by itself does not imply presence of lymphoma; but FDG-PET can help guide the decision for selecting which of many enlarged nodes in ALPS patients to biopsy when lymphoma is suspected.
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Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with Autoimmune Lymphoproliferative Syndrome.
British journal of haematology, 2005Co-Authors: V. Koneti Rao, Jennifer M Puck, Janet K Dale, Joie Davis, Thomas A. Fleisher, Faith Dugan, Jean Tretler, John K. Hurley, Sharon E. StrausAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of apoptosis associated most often with heritable FAS mutations leading to lymphadenopathy, hypersplenism and chronic refractory Autoimmune cytopenias. Mycophenolate mofetil (MMF) was used to treat cytopenias in 13 ALPS patients aged 9 months to 17 years from a cohort of 118 children (aged < 18 years) and 82 adults. Twelve responded for a median follow-up of 49 weeks (range 38-240 weeks), defined by maintenance of adequate blood counts and reduction in dosage or cessation of other immunosuppressive agents. This preliminary experience suggests that MMF may spare steroid usage in patients with ALPS-associated cytopenias.
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aberrant t cell antigen receptor mediated responses in Autoimmune Lymphoproliferative Syndrome
Clinical Immunology, 2002Co-Authors: Frederick D Goldman, Jennifer M Puck, Sharon E. Straus, Rajeev Vibhakar, Zuhair K Ballas, Clay Hollenback, Thomas W Loew, Anthony Thompson, Kejing Song, Robert T CookAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of defective lymphocyte apoptosis due to mutations of the Fas receptor and other molecules in the Fas signaling pathway. In addition to accumulation of CD4(-) CD8(-) double-negative (DN) T cells, many patients display a dysregulated cytokine pattern with dysfunctional T cells, suggesting Fas defects may impact pathways of T-cell activation/differentiation. Here, we report two novel mutations in the Fas receptor resulting in an ALPS phenotype. Utilizing flow cytometry, we found anti-CD3 activated CD4(+) T cells from these patients were incapable of fully upregulating activation markers (CD25, CD69, and CD40L) or producing interferon-gamma and IL-2. Additionally, DN T cells were unable to transduce proximal T-cell antigen receptor signals or produce cytokines. Furthermore, DN T cells overexpressed CD57 and phenotypically resembled end-stage effector cells. As DN T cells were essentially anergic, the clinical manifestations of autoimmunity are more likely to be a consequence of aberrant cytokine secretion within the CD4(+) T-cell subpopulation.
David T. Teachey - One of the best experts on this subject based on the ideXlab platform.
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Autoimmune Lymphoproliferative Syndrome: more than a FAScinating disease.
F1000Research, 2017Co-Authors: Karen L. Bride, David T. TeacheyAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is an inherited Syndrome characterized by abnormal lymphocyte survival caused by failure of apoptotic mechanisms to maintain lymphocyte homeostasis. This failure leads to the clinical manifestations of non-infectious and non-malignant lymphadenopathy, splenomegaly, and Autoimmune pathology, most commonly, Autoimmune cytopenias. Since ALPS was first characterized in the early 1990s, insights in disease biology have improved both diagnosis and management of this Syndrome. Sirolimus is the best-studied and most effective corticosteroid-sparing therapy for ALPS and should be considered first-line for patients in need of chronic treatment. This review highlights practical clinical considerations for the diagnosis and management of ALPS. Further studies could reveal new proteins and regulatory pathways that are critical for lymphocyte activation and apoptosis.
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Optimal Management of Autoimmune Lymphoproliferative Syndrome in Children
Pediatric Drugs, 2016Co-Authors: Lindsey A. George, David T. TeacheyAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of abnormal lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway. Clinical manifestations include noninfectious and nonmalignant lymphadenopathy, splenomegaly, and Autoimmune pathology—most commonly, Autoimmune cytopenias. Rarely, and in association with specific genetic mutations, patients with ALPS may go on to develop secondary lymphoid malignancies. Though ALPS is a rare disorder, it should be suspected and ruled out in children presenting with chronic and refractory multilineage cytopenias associated with nonmalignant lymphoproliferation. Revised diagnostic criteria and insights into disease biology have improved both diagnosis and treatment. Sirolimus and mycophenolate mofetil are the best-studied and most effective corticosteroid-sparing therapies for ALPS, and they should be considered first-line therapy for patients who need chronic treatment. This review highlights practical clinical considerations for diagnosis and management of ALPS.
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New advances in the diagnosis and treatment of Autoimmune Lymphoproliferative Syndrome
Current opinion in pediatrics, 2012Co-Authors: David T. TeacheyAbstract:Purpose of Review Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of disrupted lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway. Clinical manifestations include lymphadenopathy, splenomegaly, and Autoimmune cytopenias. A number of new insights have improved the understanding of the genetics and biology of ALPS. These will be discussed in this review.
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Advances in the management and understanding of Autoimmune Lymphoproliferative Syndrome (ALPS)
British journal of haematology, 2009Co-Authors: David T. Teachey, Alix E. Seif, Stephan A. GruppAbstract:Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of T cell dysregulation caused by defective Fas-mediated apoptosis. Patients with ALPS can develop a myriad of clinical manifestations including lymphadenopathy, hepatosplenomegaly, autoimmunity and increased rates of malignancy. ALPS may be more common that originally thought, and testing for ALPS should be considered in patients with unexplained lymphadenopathy, hepatosplenomegaly, and/or autoimmunity. As the pathophysiology of ALPS is better characterized, a number of targeted therapies are in preclinical development and clinical trials with promising early results. This review describes the clinical and laboratory manifestations found in ALPS patients, as well as the molecular basis for the disease and new advances in treatment.
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Treatment with sirolimus results in complete responses in patients with Autoimmune Lymphoproliferative Syndrome
British journal of haematology, 2009Co-Authors: David T. Teachey, Jack J. Bleesing, Alix E. Seif, Robert J. Greiner, Edward F. Attiyeh, John K. Choi, Catherine S. Manno, Eric F. Rappaport, Dirk Schwabe, Cecilia SheenAbstract:We hypothesized that sirolimus, an mTOR inhibitor, may be effective in patients with Autoimmune Lymphoproliferative Syndrome (ALPS) and treated patients who were intolerant to or failed other therapies. Four patients were treated for Autoimmune cytopenias; all had a rapid complete or near complete response. Two patients were treated for Autoimmune arthritis and colitis, demonstrating marked improvement. Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease. Based on these significant responses, we recommend that sirolimus be considered as second-line therapy for patients with steroid-refractory disease.
