The Experts below are selected from a list of 12144 Experts worldwide ranked by ideXlab platform
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
2011Co-Authors: Amy P. Hsu, Joie Davis, Kennichi C. Dowdell, 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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pyrimethamine treatment does not ameliorate lymphoproliferation or autoimmune disease in mrl lpr mice or in patients with autoimmune lymphoproliferative syndrome
2007Co-Authors: Koneti V Rao, Janet K Dale, Kennichi C. Dowdell, Thomas A Fleisher, Faith Dugan, Lesley Pesnicak, Victoria Hoffmann, Scott R Penzak, Nilo A Avila, Jennifer M PuckAbstract:Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of Lymphocyte Apoptosis leading to childhood onset of marked lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, and increased risk of lymphoma. Most cases are associated with heterozygous mutations in the gene encoding Fas protein. Prolonged use of immunosuppressive drugs that do ameliorate its autoimmune complications fail to consistently lessen lymphoproliferation in ALPS. A case series had described children with ALPS, whose spleens (SPL) and lymph nodes decreased in size when treated weekly with pyrimethamine and sulfadoxine; parallel in vitro studies showed only pyrimethamine to promote Apoptosis. On the basis of that experience, we undertook additional in vitro Lymphocyte Apoptosis assays, and measured SPL weights, Lymphocyte numbers, and immunophenotypes in Fas-deficient MRL/lpr−/− mice to gain further insights into the utility of combined pyrimethamine/sulfadoxine or pyrimethamine alone. Moreover, seven children with ALPS enrolled in a study of escalating dose of pyrimethamine alone given twice weekly for 12 weeks to determine if their lymphadenopathy and/or splenomegaly would diminish, as assessed by standardized computerized tomography. Neither pyrimethamine alone or with sulfadoxine in the MRL/lpr−/− mice, nor pyrimethamine alone in ALPS patients proved efficacious. We conclude that these drugs do not warrant further use empirically or as part of clinical trials in ALPS Type Ia as a lympholytic agent. Am. J. Hematol., 2007. Published 2007 Wiley-Liss, Inc.
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pleiotropic defects in Lymphocyte activation caused by caspase 8 mutations lead to human immunodeficiency
2002Co-Authors: Hyung J Chu, Lixi Zheng, Manzoo Ahmad, Christina K Speirs, Jane K Dale, Jennifer M Puck, Richard M Siegel, Ji Wang, Joie DavisAbstract:Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, Apoptosis counters the proliferation of Lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity1,2. The CD95 (Fas, Apo-1) receptor triggers Lymphocyte Apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex3,4. Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective Lymphocyte Apoptosis, lymphadenopathy, splenomegaly and autoimmunity5,6,7,8,9,10,11,12,13,14. Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective Lymphocyte Apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T Lymphocytes, B Lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive Lymphocytes.
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the development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline fas mutations and defective Lymphocyte Apoptosis
2001Co-Authors: Stephen E Straus, Jennifer M Puck, Janet K Dale, Michael C Sneller, Elaine S Jaffe, Keith B Elkon, Angela Rosenwolff, Anke M J Peters, Claire W Hallahan, Jin WangAbstract:Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of Lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or Apoptosis, of activated Lymphocytes. Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3(+)CD4(-)CD8(-) T-cell-receptor alpha/beta cells by flow cytometry, nucleotide sequences of the gene encoding Fas (APT1, TNFRSF6), and the percentage of Lymphocytes undergoing Apoptosis in vitro. Of 223 members of 39 families, 130 individuals possessed heterozygous germline Fas mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected (each P <.001). Investigation of these 10 patients and their relatives with Fas mutations revealed that all had defective Lymphocyte Apoptosis and most had other features of ALPS. The tumor cells retained the heterozygous Fas mutations found in the peripheral blood and manifested defective Fas-mediated killing. These data implicate a role for Fas-mediated Apoptosis in preventing B-cell and T-cell lymphomas. Inherited defects in receptor-mediated Lymphocyte Apoptosis represent a newly appreciated risk factor for lymphomas.
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the development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline fas mutations and defective Lymphocyte Apoptosis
2001Co-Authors: Stephen E Straus, Jennifer M Puck, Janet K Dale, Michael C Sneller, Elaine S Jaffe, Keith B Elkon, Angela Rosenwolff, Anke M J Peters, Claire W Hallahan, Jin WangAbstract:Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of Lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or Apoptosis, of activated Lymphocytes. Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3+CD4−CD8− T-cell–receptor α/β cells by flow cytometry, nucleotide sequences of the gene encoding Fas ( APT1 , TNFRSF6), and the percentage of Lymphocytes undergoing Apoptosis in vitro. Of 223 members of 39 families, 130 individuals possessed heterozygous germline Fas mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected (each P < .001). Investigation of these 10 patients and their relatives with Fas mutations revealed that all had defective Lymphocyte Apoptosis and most had other features of ALPS. The tumor cells retained the heterozygous Fas mutations found in the peripheral blood and manifested defective Fas-mediated killing. These data implicate a role for Fas-mediated Apoptosis in preventing B-cell and T-cell lymphomas. Inherited defects in receptor-mediated Lymphocyte Apoptosis represent a newly appreciated risk factor for lymphomas.
Michael J Lenardo - One of the best experts on this subject based on the ideXlab platform.
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a rapid ex vivo clinical diagnostic assay for fas receptor induced t Lymphocyte Apoptosis
2013Co-Authors: Bernice Lo, Madhu Ramaswamy, Joie Davis, Susan Price, Richard M Siegel, Michael J LenardoAbstract:Deleterious mutations in genes involved in the Fas Apoptosis pathway lead to Autoimmune Lymphoproliferative Syndrome (ALPS). Demonstration of an Apoptosis defect is critical for the diagnosis and study of ALPS. The traditional in vitro Apoptosis assay, however, requires a week of experimental procedures. Here, we show that defects in Fas-induced Apoptosis in PBMCs can be evaluated directly ex vivo using multicolor flow cytometry to analyze the Apoptosis of effector memory T cells, a Fas-sensitive subset of PBMCs. This method allowed us to sensitively quantify defective Apoptosis in ALPS patients within a few hours. Some ALPS patients (ALPS-sFAS) without germline mutations have somatic mutations in Fas specifically in double-negative αβ T cells (DNTs), an unusual Lymphocyte population that is characteristically expanded in ALPS. Since DNTs have been notoriously difficult to culture, defective Apoptosis has not been previously demonstrated for ALPS-sFAS patients. Using our novel ex vivo Apoptosis assay, we measured Fas-induced Apoptosis of DNTs for the first time and found that ALPS-sFAS patients had significant Apoptosis defects in these cells compared to healthy controls. Hence, this rapid Apoptosis assay can expedite the diagnosis of new ALPS patients, including those with somatic mutations, and facilitate clinical and molecular investigation of these diseases.
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autoimmune lymphoproliferative syndrome types i ii and beyond
2001Co-Authors: Hyung J Chun, Michael J LenardoAbstract:An essential element in the maintenance of homeostasis of the immune system is the capacity for Apoptosis, or programmed cell death. Apoptosis limits the accumulation of Lymphocytes, and minimizes reactions against self-antigen that can lead to autoimmunity1,2. Lymphocyte Apoptosis occurs in at least two major forms: antigen receptor engagement and lymphokine withdrawal. These forms of death are controlled in a negative feedback mechanism termed propriocidal regulation1,3. Antigen-mediated death of Lymphocytes is regulated by Fas (CD95/APO-1), tumor necrosis factor receptor (TNFR), and related molecules4-6. Passive Apoptosis via lymphokine withdrawal may result from the cytoplasmic activation of caspases that is closely regulated by the mitochondria and the members of the Bcl-2 family of proteins. Apoptosis of other immune cells such as dendritic cells may also contribute to immune homeostasis7.
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an inherited disorder of Lymphocyte Apoptosis the autoimmune lymphoproliferative syndrome
1999Co-Authors: Sharon E Straus, Jennifer M Puck, Michael J Lenardo, Michael C Sneller, Warren StroberAbstract:The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that regulate Lymphocyte homeostasis and underlie the development of autoimmunity. This syndrome arises early in childhood in persons who inherit mutations in genes that mediate Apoptosis, or programmed cell death. The timely deletion of Lymphocytes is a way to prevent their accumulation and the persistence of cells that can react against the body's own antigens. In ALPS, defective Lymphocyte Apoptosis permits chronic, nonmalignant adenopathy and splenomegaly; the survival of normally uncommon "double-negative" CD3+ CD4- CD8- T cells; and the development of autoimmune disease. Most cases of ALPS involve heterozygous mutations in the Lymphocyte surface protein Fas that impair a major apoptotic pathway. Detailed immunologic investigations of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenotype; this provides a rational explanation for the humoral autoimmunity typical of patients with ALPS. Prospective evaluations of 26 patients and their families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. Defective Apoptosis may also contribute to a heightened risk for lymphoma.
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mature t Lymphocyte Apoptosis immune regulation in a dynamic and unpredictable antigenic environment
1999Co-Authors: Michael J Lenardo, Richard M Siegel, Jin Wang, Francis Kaming Chan, Felicita Hornung, Hugh I Mcfarland, Lixin ZhengAbstract:Apoptosis of mature T Lymphocytes preserves peripheral homeostasis and tolerance by countering the profound changes in the number and types of T cells stimulated by diverse antigens. T cell Apoptosis occurs in at least two major forms: antigen-driven and lymphokine withdrawal. These forms of death are controlled in response to local levels of IL-2 and antigen in a feedback mechanism termed propriocidal regulation. Active antigen-driven death is mediated by the expression of death cytokines such as FasL and TNF. These death cytokines engage specific receptors that assemble caspase-activating protein complexes. These signaling complexes tightly regulate cell death but are vulnerable to inherited defects. Passive lymphokine withdrawal death may result from the cytoplasmic activation of caspases that is regulated by mitochondria and the Bcl-2 protein. The human disease, Autoimmune Lymphoproliferative Syndrome (ALPS) is due to dominant-interfering mutations in the Fas/APO-1/CD95 receptor and other components of the death pathway. The study of ALPS patients reveals the necessity of Apoptosis for preventing autoimmunity and allows the genetic investigation of Apoptosis in humans. Immunological, cellular, and molecular evidence indicates that throughout the life of a T cell, Apoptosis may be evoked in excessive, harmful, or useless clonotypes to preserve a healthy and balanced immune system.
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the clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a fas mutation that impairs Lymphocyte Apoptosis
1998Co-Authors: Anthony J Infante, Stephen E Straus, Lindsay A Middelton, Michael J Lenardo, Jin Wang, Thomas A Fleisher, Howard A Britton, Thomas Denapoli, Christine E Jackson, Jennifer M PuckAbstract:Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic, histologically benign splenomegaly and generalized lymphadenopathy, hypergammaglobulinemia, and autoantibody formation. ALPS has been attributed to defective programmed cell death of Lymphocytes, most often arising as a result of mutations in the gene encoding the Lymphocyte Apoptosis receptor Fas/APO-l/CD95. We identified a novel mutation in the intracellular Apoptosis signaling domain of Fas in 11 members of a family, individual members of which have been monitored for up to 25 years, with 1 or more features of ALPS. This study of a large number of family members carrying the same Fas defect demonstrates that ALPS is inherited in an autosomal dominant fashion but with a high degree of variability in clinical expression. Although 1 affected individual died of postsplenectomy sepsis and 1 has been treated for lymphoma, the Fas mutation in this family has been compatible with a healthy adulthood, as clinical features of ALPS have receded with increasing age.
Xiaoming Deng - One of the best experts on this subject based on the ideXlab platform.
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ginsenoside rg1 improves survival in a murine model of polymicrobial sepsis by suppressing the inflammatory response and Apoptosis of Lymphocytes
2013Co-Authors: Yun Zou, Jiali Zhu, Tianzhu Tao, Ye Tian, Lijun Cao, Xiaoming DengAbstract:Abstract Background Unbalanced inflammatory response and Lymphocyte Apoptosis are the main reasons for high mortality in patients with sepsis. Ginsenoside Rg1 (Rg1), the most important component isolated from Panax ginseng , has long been used to treat inflammatory and immune-related diseases. We designed this study to investigate the therapeutic effect of this agent on cecal ligation and puncture (CLP)-induced sepsis in mice. Materials and methods We randomly divided C57BL/6 mice into four experimental groups: sham, sham plus Rg1, CLP, and CLP plus Rg1. We intravenously injected Rg1 (20 mg/kg) 1 h after CLP and evaluated survival, bacterial clearance, cytokine production, histology, neutrophil emigration, and Lymphocyte Apoptosis. Results Our study showed that treatment with Rg1 significantly improved survival in septic mice ( P Conclusions Ginsenoside Rg1 has a protective role against CLP-induced polymicrobial sepsis by attenuating the proinflammatory response, enhancing innate immunity and preserving adaptive immunity. Rg1 could be a promising new agent for treatment of sepsis.
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ulinastatin improves survival of septic mice by suppressing inflammatory response and Lymphocyte Apoptosis
2013Co-Authors: Na Huang, Fei Wang, Yingwei Wang, Jiong Hou, Xiaoming DengAbstract:Abstract Background Sepsis involves imbalance between the proinflammatory and antiinflammatory response to bacterial insults. Ulinastatin (UTI) is a serine protease inhibitor and reportedly exhibits antiinflammatory properties aside from its blocking of the protease pathway both in vitro and in vivo . This study was designed to investigate the potential therapeutic efficacy of UTI for sepsis. Materials and methods Adult C57BL/6 male mice were divided into three groups: sham group, cecal ligation and puncture (CLP) group, and CLP + UTI group. Acute septic peritonitis was induced by CLP. Saline and UTI (100,000 U/kg) were intravenously injected 30 min after CLP in CLP and CLP + UTI groups, respectively. Samples were collected for further analysis 24 h after surgery. Results UTI administration significantly improved 7-d survival; ameliorated morphologic damage and weight loss in the spleen and thymus; decreased serum tumor necrosis factor α, interleukin-6, and interleukin-10 (IL-10) levels; increased the number of T and B cells in peripheral blood, spleen, and thymus; and inhibited T-cell Apoptosis in the thymus and spleen in septic mice. Conclusions UTI exerted a protective effect against sepsis by suppressing inflammatory response and Lymphocyte Apoptosis.
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baicalin improves survival in a murine model of polymicrobial sepsis via suppressing inflammatory response and Lymphocyte Apoptosis
2012Co-Authors: Jiali Zhu, Jiafeng Wang, Ying Sheng, Yun Zou, Fei Wang, Jingsheng Lou, Xiaohua Fan, Rui Bao, Feng Chen, Xiaoming DengAbstract:Background An imbalance between overwhelming inflammation and Lymphocyte Apoptosis is the main cause of high mortality in patients with sepsis. Baicalin, the main active ingredient of the Scutellaria root, exerts anti-inflammatory, anti-apoptotic, and even antibacterial properties in inflammatory and infectious diseases. However, the therapeutic effect of baicalin on polymicrobial sepsis remains unknown.
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pd l1 blockade improves survival in experimental sepsis by inhibiting Lymphocyte Apoptosis and reversing monocyte dysfunction
2010Co-Authors: Yanyan Zhang, Jingsheng Lou, Xiaoming Deng, Ying Zhou, Keming Zhu, Xiaojian Wan, Zailong CaiAbstract:Introduction Lymphocyte Apoptosis and monocyte dysfunction play a pivotal role in sepsis-induced immunosuppression. Programmed death-1 (PD1) and its ligand programmed death ligand-1 (PD-L1) exert inhibitory function by regulating the balance among T cell activation, tolerance, and immunopathology. PD-1 deficiency or blockade has been shown to improve survival in murine sepsis. However, PD-L1 and PD-1 differ in their expression patterns and the role of PD-L1 in sepsis-induced immunosuppression is still unknown.
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pd l1 blockade improves survival in experimental sepsis by inhibiting Lymphocyte Apoptosis and reversing monocyte dysfunction
2010Co-Authors: Yanyan Zhang, Jingsheng Lou, Xiaoming Deng, Ying Zhou, Keming Zhu, Xiaojian Wan, Zailong CaiAbstract:Introduction: Lymphocyte Apoptosis and monocyte dysfunction play a pivotal role in sepsis-induced immunosuppression. Programmed death-1 (PD1) and its ligand programmed death ligand-1 (PD-L1) exert inhibitory function by regulating the balance among T cell activation, tolerance, and immunopathology. PD-1 deficiency or blockade has been shown to improve survival in murine sepsis. However, PD-L1 and PD-1 differ in their expression patterns and the role of PD-L1 in sepsis-induced immunosuppression is still unknown. Methods: Sepsis was induced in adult C57BL/6 male mice via cecal ligation and puncture (CLP). The expression of PD-1 and PD-L1 expression on peripheral T cells, B cells and monocytes were measured 24 hours after CLP or sham surgery. Additionally, the effects of anti-PD-L1 antibody on Lymphocyte number, Apoptosis of spleen and thymus, activities of caspase-8 and caspase-9, cytokine production, bacterial clearance, and survival were determined. Results: Expression of PD-1 on T cells, B cells and monocytes and PD-L1 on B cells and monocytes were upregulated in septic animals compared to sham-operated controls. PD-L1 blockade significantly improved survival of CLP mice. Anti-PD-L1 antibody administration prevented sepsis-induced depletion of Lymphocytes, increased tumor necrosis factor (TNF)-a and interleukin (IL)-6 production, decreased IL-10 production, and enhanced bacterial clearance. Conclusions: PD-L1 blockade exerts a protective effect on sepsis at least partly by inhibiting Lymphocyte Apoptosis and reversing monocyte dysfunction. Anti-PD-L1 antibody administration may be a promising therapeutic strategy for sepsis-induced immunosuppression.
Richard S Hotchkiss - One of the best experts on this subject based on the ideXlab platform.
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mechanisms and consequences of ebolavirus induced Lymphocyte Apoptosis
2010Co-Authors: Steven B Bradfute, Richard S Hotchkiss, Paul E Swanson, Mark A Smith, Eizo Watanabe, Jonathan E Mcdunn, Sina BavariAbstract:Ebolavirus (EBOV) is a member of the filovirus family and causes severe hemorrhagic fever, resulting in death in up to 90% of infected humans. EBOV infection induces massive bystander Lymphocyte Apoptosis; however, neither the cellular apoptotic pathway(s) nor the systemic implications of Lymphocyte Apoptosis in EBOV infection are known. In this study, we show data suggesting that EBOV-induced Lymphocyte Apoptosis in vivo occurs via both the death receptor (extrinsic) and mitochondrial (intrinsic) pathways, as both Fas-associated death domain dominant negative transgenic mice and mice overexpressing bcl-2 were resistant to EBOV-induced Lymphocyte Apoptosis. Surprisingly, inhibiting Lymphocyte Apoptosis during EBOV infection did not result in improved animal survival. Furthermore, we show for the first time that hepatocyte Apoptosis likely occurs in EBOV infection, and that mice lacking the proapoptotic genes Bim and Bid had reduced hepatocyte Apoptosis and liver enzyme levels postinfection. Collectively, these data suggest that EBOV induces multiple proapoptotic stimuli and that blocking Lymphocyte Apoptosis is not sufficient to improve survival in EBOV infection. These data suggest that hepatocyte Apoptosis may play a role in the pathogenesis of EBOV infection, whereas Lymphocyte Apoptosis appears to be nonessential for EBOV disease progression.
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deletion of myd88 markedly attenuates sepsis induced t and b Lymphocyte Apoptosis but worsens survival
2008Co-Authors: Octavia M Peckpalmer, Katherine Chang, Christopher G. Davis, Jonathan E Mcdunn, Jacqueline Unsinger, Richard S HotchkissAbstract:Sepsis induces widespread Lymphocyte Apoptosis, resulting in impaired immune defenses and increased morbidity and mortality. There are multiple potential triggers or signaling molecules involved in mediating death signals. Elucidating the specific signaling pathways that are involved in mediating Lymphocyte Apoptosis may lead to improved therapies of this lethal disorder. We investigated a number of key cellular receptors and intracellular signaling pathways that may be responsible for apoptotic cell death. Specifically, we investigated the role of pathogen-associated molecular patterns (TLR2, TLR4, and IL-1R), intracellular signaling proteins (MyD88 and TRIF), cytoplasmic transcription factors (STAT1 and STAT4), and the MAPK pathway (JNK1) in sepsis-induced Lymphocyte Apoptosis. Studies were performed in the cecal ligation and puncture (CLP) model of sepsis using specific gene-targeted deletions. CLP-induced Lymphocyte Apoptosis was evaluated 20 h post-operation by active caspase-3 and TUNEL staining. Surprisingly, the only genetic construct that ameliorated T and B Lymphocyte sepsis-induced Apoptosis ( approximately 80% and 85%, respectively) occurred in MyD88(-/-) mice. Despite the marked decrease in sepsis-induced Apoptosis, MyD88(-/-) mice had a worsened survival. In conclusion, Lymphocyte death in sepsis likely involves multiple pathogen-sensing receptors and redundant signaling pathways. MyD88 was effective in blocking Apoptosis, as it is essential in mediating most pathogen recognition pathways; however, MyD88 is also critical for host survival in a model of severe peritonitis.
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Agonistic Monoclonal Antibody Against CD40 Receptor Decreases Lymphocyte Apoptosis and Improves Survival in Sepsis
2006Co-Authors: Steven J. Schwulst, Mitchell H. Grayson, Peter J. Dipasco, Christopher G. Davis, Tejal S. Brahmbhatt, Thomas A. Ferguson, Richard S HotchkissAbstract:Sepsis causes a marked Apoptosis-induced depletion of Lymphocytes. The degree of Lymphocyte Apoptosis during sepsis strongly correlates with survival. CD40, a member of the TNFR family, is expressed on APCs and has potent antiapoptotic activity. In this study we determined whether an agonistic Ab against CD40 could protect Lymphocytes from sepsis-induced Apoptosis. Secondly, we examined potential antiapoptotic mechanisms of the putative protection. Lastly, we aimed to determine whether anti-CD40 treatment could improve survival in sepsis. CD1 mice were made septic by the cecal ligation and puncture method and treated postoperatively with anti-CD40 Ab. Treatment with anti-CD40 completely abrogated sepsis-induced splenic B cell death and, surprisingly, decreased splenic and thymic T cell death as well ( p + CD8 − T cells were the predominant subtype of T cells expressing CD40 receptor during sepsis. Additionally, the antiapoptotic protein Bcl-x L was found to be markedly increased in splenic B and T cells as well as in thymic T cells after treatment with anti-CD40 Ab ( p p = 0.05). In conclusion, anti-CD40 treatment increases Bcl-x L , provides nearly complete protection against sepsis-induced Lymphocyte Apoptosis, and improves survival in sepsis.
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tat bh4 and tat bcl xl peptides protect against sepsis induced Lymphocyte Apoptosis in vivo
2006Co-Authors: Richard S Hotchkiss, Katherine Chang, Steven J. Schwulst, Christopher G. Davis, Kevin W Mcconnell, Kristin E Bullok, Jeffrey C Dunne, Gunnar P H Dietz, Mathias Bahr, Jonathan E McdunnAbstract:Apoptosis is a key pathogenic mechanism in sepsis that induces extensive death of Lymphocytes and dendritic cells, thereby contributing to the immunosuppression that characterizes the septic disorder. Numerous animal studies indicate that prevention of Apoptosis in sepsis improves survival and may represent a potential therapy for this highly lethal disorder. Recently, novel cell-penetrating peptide constructs such as HIV-1 TAT basic domain and related peptides have been developed to deliver bioactive cargoes and peptides into cells. In the present study, we investigated the effects of sepsis-induced Apoptosis in Bcl-x(L) transgenic mice and in wild-type mice treated with an antiapoptotic TAT-Bcl-x(L) fusion protein and TAT-BH4 peptide. Lymphocytes from Bcl-x(L) transgenic mice were resistant to sepsis-induced Apoptosis, and these mice had a approximately 3-fold improvement in survival. TAT-Bcl-x(L) and TAT-BH4 prevented Escherichia coli-induced human Lymphocyte Apoptosis ex vivo and markedly decreased Lymphocyte Apoptosis in an in vivo mouse model of sepsis. In conclusion, TAT-conjugated antiapoptotic Bcl-2-like peptides may offer a novel therapy to prevent Apoptosis in sepsis and improve survival.
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prevention of Lymphocyte Apoptosis a potential treatment of sepsis
2005Co-Authors: Richard S Hotchkiss, Craig M Coopersmith, Irene E KarlAbstract:Sepsis is the leading cause of death in surgical intensive care units and is a major cause of morbidity and mortality in neonatal and medical intensive care units. The Centers for Disease Control and Prevention estimates that, in the United States alone, ∼500,000 people develop sepsis and 175,000 people die each year. Sepsis is a growing problem; its incidence has tripled from 1972 to 1992. Recently, Apoptosis has been identified as an important mechanism of cell death in animal models of sepsis and endotoxemia. During sepsis, there is extensive apoptotic death of Lymphocytes and gastrointestinal epithelial cells. The extensive apoptotic death of Lymphocytes is likely an important cause of the profound immunosuppression that is a hallmark of patients with sepsis. The Apoptosis of gastrointestinal epithelial cells may compromise the integrity of the bowel wall, resulting in translocation of bacteria or endotoxins into the systemic circulation. The potential importance of Apoptosis in the pathophysiology of sepsis is illustrated by results from animal models that demonstrate that blocking Lymphocyte Apoptosis improves survival in sepsis. A variety of strategies to inhibit Apoptosis may ultimately provide an effective therapy for this highly lethal disorder.
Warren Strober - One of the best experts on this subject based on the ideXlab platform.
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an inherited disorder of Lymphocyte Apoptosis the autoimmune lymphoproliferative syndrome
1999Co-Authors: Sharon E Straus, Jennifer M Puck, Michael J Lenardo, Michael C Sneller, Warren StroberAbstract:The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that regulate Lymphocyte homeostasis and underlie the development of autoimmunity. This syndrome arises early in childhood in persons who inherit mutations in genes that mediate Apoptosis, or programmed cell death. The timely deletion of Lymphocytes is a way to prevent their accumulation and the persistence of cells that can react against the body's own antigens. In ALPS, defective Lymphocyte Apoptosis permits chronic, nonmalignant adenopathy and splenomegaly; the survival of normally uncommon "double-negative" CD3+ CD4- CD8- T cells; and the development of autoimmune disease. Most cases of ALPS involve heterozygous mutations in the Lymphocyte surface protein Fas that impair a major apoptotic pathway. Detailed immunologic investigations of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenotype; this provides a rational explanation for the humoral autoimmunity typical of patients with ALPS. Prospective evaluations of 26 patients and their families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. Defective Apoptosis may also contribute to a heightened risk for lymphoma.
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clinical immunologic and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal Lymphocyte Apoptosis
1997Co-Authors: Michael C Sneller, Janet K Dale, Lindsay A Middelton, Warren Strober, Jin Wang, Youngnim Choi, Thomas A Fleisher, Megan S Lim, Elaine S Jaffe, Jennifer M PuckAbstract:Programmed cell death (Apoptosis) of activated Lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating Lymphocyte Apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature Lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective Lymphocyte Apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, Lymphocyte phenotyping, genotyping, and in vitro assays for Lymphocyte Apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4−CD8− T cells that express the α/β T-cell receptor (TCR). All patients showed defective Lymphocyte Apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated Lymphocyte Apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of Lymphocyte Apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that Apoptosis of activated Lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired Lymphocyte Apoptosis in only a subset of patients with ALPS.
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dominant interfering fas gene mutations impair Apoptosis in a human autoimmune lymphoproliferative syndrome
1995Co-Authors: Galen H Fisher, Fredric J Rosenberg, Stephen E Straus, Janet K Dale, Lindsay A Middelton, Warren Strober, Michael J Lenardo, Jennifer M PuckAbstract:Abstract Five unrelated children are described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3 + CD4 − CD8 − Lymphocytes. These findings, suggesting a genetic defect in the ability of T Lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of Lymphocyte Apoptosis. Each child had defective Fas-mediated T Lymphocyte Apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when coaxpressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. The occurrence of Fas mutations together with abnormal T cell Apoptosis in ALPS patients suggests an involvement of Fas in this recently recognized disorder of Lymphocyte homeostasis and peripheral self-tolerance.
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dominant interfering fas gene mutations impair Apoptosis in a human autoimmune lymphoproliferative syndrome
1995Co-Authors: Galen H Fisher, Fredric J Rosenberg, Stephen E Straus, Janet K Dale, Lindsay A Middelton, Warren Strober, Michael J Lenardo, Albert Y Lin, Jennifer M PuckAbstract:Five unrelated children are described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3+CD4-CD8- Lymphocytes. These findings, suggesting a genetic defect in the ability of T Lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of Lymphocyte Apoptosis. Each child had defective Fas-mediated T Lymphocyte Apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when coexpressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. The occurrence of Fas mutations together with abnormal T cell Apoptosis in ALPS patients suggests an involvement of Fas in this recently recognized disorder of Lymphocyte homeostasis and peripheral self-tolerance.
