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Angelo Ravelli - One of the best experts on this subject based on the ideXlab platform.
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Macrophage Activation Syndrome
Hematology oncology clinics of North America, 2015Co-Authors: Angelo Ravelli, Sergio Davì, Francesca Minoia, Alberto Martini, Randy Q. CronAbstract:Macrophage Activation syndrome (MAS) is a potentially life-threatening complication of rheumatic disorders that occurs most commonly in systemic juvenile idiopathic arthritis. In recent years, there have been several advances in the understanding of the pathophysiology of MAS. Furthermore, new classification criteria have been developed. Although the place of cytokine blockers in the management of MAS is still unclear, interleukin-1 inhibitors represent a promising adjunctive therapy, particularly in refractory cases.
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clinical features and correct diagnosis of Macrophage Activation syndrome
Expert Review of Clinical Immunology, 2015Co-Authors: Randy Q. Cron, Sergio Davì, Francesca Minoia, Angelo RavelliAbstract:Macrophage Activation syndrome (MAS) is increasingly recognized among febrile hospitalized patients. Clinically, MAS resembles multiorgan dysfunction and shock. Laboratory features include hepatobiliary dysfunction, coagulopathy, pancytopenia, hyperferritinemia and markers of immune Activation. Pathologically, hemophagocytosis is commonly seen but is only present in 60% of MAS patients. MAS, or secondary hemophagocytic lymphohistiocytosis (HLH), is triggered by infectious (e.g., herpes family viruses), rheumatologic (e.g., systemic lupus erythematosus [SLE]) and oncologic (e.g., T-cell leukemia) conditions. Formal HLH criteria, while specific, are frequently insensitive for MAS diagnosis. Thus, disease-specific (e.g., SLE) and generic MAS criteria have been published. Recently, novel criteria for MAS in children with systemic juvenile idiopathic arthritis (sJIA) were developed and are a key focus of this review.
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Macrophage Activation syndrome in juvenile systemic lupus erythematosus: an under-recognized complication?
Lupus, 2007Co-Authors: Alejandra Beatriz Pringe, Nicolino Ruperto, Alberto Martini, L Trail, Antonella Buoncompagni, Anna Loy, Luciana Breda, Angelo RavelliAbstract:Macrophage Activation syndrome (MAS) is a life-threatening complication of rheumatic diseases that is thought to be caused by the Activation and uncontrolled proliferation of T lymphocytes and macr...
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Macrophage Activation syndrome.
Current opinion in rheumatology, 2002Co-Authors: Angelo RavelliAbstract:Macrophage Activation syndrome (MAS) is a serious complication of childhood systemic inflammatory disorders that is thought to be caused by excessive Activation and proliferation of T lymphocytes and Macrophages. Recent findings in hemophagocytic lymphohistiocytosis, a disease that is clinically similar to MAS, highlight the possible pathogenetic role of a defective function of perforin, a protein involved in the cytolytic processes and control of lymphocyte proliferation. Although the clinical features of MAS have been well documented, early diagnosis can be difficult. Measurement of the serum ferritin level may assist in the diagnosis and may be a useful indicator of disease activity, therapy response, and prognosis. The recognition that MAS belongs to the secondary or reactive hemophagocytic syndromes has led to the proposal to rename it according to the contemporary classification of histiocytic disorders. Cyclosporin A has been found effective in patients with corticosteroid-resistant MAS. A recent report has suggested that etanercept may be a useful adjunctive therapeutic agent.
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Macrophage Activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine
The Journal of Pediatrics, 1996Co-Authors: Angelo Ravelli, Fabrizio De Benedetti, S Viola, Alberto MartiniAbstract:A Macrophage Activation syndrome, possibly related to methotrexate toxicity, developed in a boy with systemic juvenile rheumatoid arthritis. Corticosteroid administration was ineffective, whereas a prompt response to cyclosporine was observed. Two months later, Pneumocystis carinii pneumonia developed.
Randy Q. Cron - One of the best experts on this subject based on the ideXlab platform.
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Macrophage Activation Syndrome
Hematology oncology clinics of North America, 2015Co-Authors: Angelo Ravelli, Sergio Davì, Francesca Minoia, Alberto Martini, Randy Q. CronAbstract:Macrophage Activation syndrome (MAS) is a potentially life-threatening complication of rheumatic disorders that occurs most commonly in systemic juvenile idiopathic arthritis. In recent years, there have been several advances in the understanding of the pathophysiology of MAS. Furthermore, new classification criteria have been developed. Although the place of cytokine blockers in the management of MAS is still unclear, interleukin-1 inhibitors represent a promising adjunctive therapy, particularly in refractory cases.
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clinical features and correct diagnosis of Macrophage Activation syndrome
Expert Review of Clinical Immunology, 2015Co-Authors: Randy Q. Cron, Sergio Davì, Francesca Minoia, Angelo RavelliAbstract:Macrophage Activation syndrome (MAS) is increasingly recognized among febrile hospitalized patients. Clinically, MAS resembles multiorgan dysfunction and shock. Laboratory features include hepatobiliary dysfunction, coagulopathy, pancytopenia, hyperferritinemia and markers of immune Activation. Pathologically, hemophagocytosis is commonly seen but is only present in 60% of MAS patients. MAS, or secondary hemophagocytic lymphohistiocytosis (HLH), is triggered by infectious (e.g., herpes family viruses), rheumatologic (e.g., systemic lupus erythematosus [SLE]) and oncologic (e.g., T-cell leukemia) conditions. Formal HLH criteria, while specific, are frequently insensitive for MAS diagnosis. Thus, disease-specific (e.g., SLE) and generic MAS criteria have been published. Recently, novel criteria for MAS in children with systemic juvenile idiopathic arthritis (sJIA) were developed and are a key focus of this review.
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genetic defects in cytolysis in Macrophage Activation syndrome
Current Rheumatology Reports, 2014Co-Authors: Mingce Zhang, Alexei A. Grom, Bita Shakoory, Edward M Behrens, Prescott T Atkinson, Randy Q. CronAbstract:Macrophage Activation syndrome (MAS), typically presenting beyond the first year of life, is an often lethal cousin of familial hemophagocytic lymphohistiocytosis (fHLH). Defects in natural killer (NK) cell and CD8 T cell cytotoxicity result in a pro-inflammatory cytokine storm, cytopenia, coagulopathy, and multi-organ system dysfunction. MAS can occur in association with infections (herpes viruses), cancer (leukemia), immune deficient states (post-transplantation), and in autoimmune (systemic lupus erythematosus) and autoinflammatory conditions (systemic juvenile idiopathic arthritis). The distinction between fHLH, the result of homozygous defects in cytolytic pathway genes, and MAS is becoming blurred with the identification of single or multiple mutations in the same cytolytic pathway genes in patients with later onset MAS. Here, we review the literature and present novel cytolytic pathway gene mutations identified in children with MAS. We study the inhibitory effect of one these novel mutations on NK cell function to suggest a direct link between fHLH and MAS.
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occult Macrophage Activation syndrome in patients with systemic juvenile idiopathic arthritis
The Journal of Rheumatology, 2007Co-Authors: Edward M Behrens, Timothy Beukelman, Michele Paessler, Randy Q. CronAbstract:Objective. Macrophage Activation syndrome (MAS) is a well described, but purportedly uncommon manifestation of systemic juvenile idiopathic arthritis (SJIA). There is evidence to suggest that Macrophage Activation is integral to the pathogenesis of SJIA. Accordingly, many patients with SJIA may have evidence of mild MAS that is not appreciated clinically. We investigated the prevalence of occult MAS in children with SJIA by reviewing bone marrow aspirates (BMA). Methods. Patients diagnosed with SJIA who underwent bone marrow aspiration were identified retrospectively. Patients admitted with a diagnosis of fever of unknown origin and discharged with a diagnosis other than SJIA or malignancy, and who had a BMA, were identified as controls. The BMA were reviewed by a single hematopathologist for evidence of MAS, ranging from activated Macrophages to frank hemophagocytic cells. Results. Eight of 15 (53%) patients with SJIA had BMA suggestive of MAS. Two of 15 patients (13%) were diagnosed clinically with MAS. Three patients (20%) were noted to have frank hemophagocytosis, only one of whom was diagnosed with MAS clinically. There were no statistically significant differences in the laboratory values for the patients with and without evidence of MAS on BMA. There was no evidence of increased Macrophage activity or hemophagocytosis in any of the control BMA. Conclusion. Occult MAS appears to be common in patients with SJIA who undergo BMA. This suggests that Macrophage Activation may be integral to the pathogenesis of SJIA, with implications for treatment.
Alberto Martini - One of the best experts on this subject based on the ideXlab platform.
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Macrophage Activation Syndrome
Hematology oncology clinics of North America, 2015Co-Authors: Angelo Ravelli, Sergio Davì, Francesca Minoia, Alberto Martini, Randy Q. CronAbstract:Macrophage Activation syndrome (MAS) is a potentially life-threatening complication of rheumatic disorders that occurs most commonly in systemic juvenile idiopathic arthritis. In recent years, there have been several advances in the understanding of the pathophysiology of MAS. Furthermore, new classification criteria have been developed. Although the place of cytokine blockers in the management of MAS is still unclear, interleukin-1 inhibitors represent a promising adjunctive therapy, particularly in refractory cases.
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Macrophage Activation syndrome in juvenile systemic lupus erythematosus: an under-recognized complication?
Lupus, 2007Co-Authors: Alejandra Beatriz Pringe, Nicolino Ruperto, Alberto Martini, L Trail, Antonella Buoncompagni, Anna Loy, Luciana Breda, Angelo RavelliAbstract:Macrophage Activation syndrome (MAS) is a life-threatening complication of rheumatic diseases that is thought to be caused by the Activation and uncontrolled proliferation of T lymphocytes and macr...
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Macrophage Activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine
The Journal of Pediatrics, 1996Co-Authors: Angelo Ravelli, Fabrizio De Benedetti, S Viola, Alberto MartiniAbstract:A Macrophage Activation syndrome, possibly related to methotrexate toxicity, developed in a boy with systemic juvenile rheumatoid arthritis. Corticosteroid administration was ineffective, whereas a prompt response to cyclosporine was observed. Two months later, Pneumocystis carinii pneumonia developed.
Alexei A. Grom - One of the best experts on this subject based on the ideXlab platform.
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genetic defects in cytolysis in Macrophage Activation syndrome
Current Rheumatology Reports, 2014Co-Authors: Mingce Zhang, Alexei A. Grom, Bita Shakoory, Edward M Behrens, Prescott T Atkinson, Randy Q. CronAbstract:Macrophage Activation syndrome (MAS), typically presenting beyond the first year of life, is an often lethal cousin of familial hemophagocytic lymphohistiocytosis (fHLH). Defects in natural killer (NK) cell and CD8 T cell cytotoxicity result in a pro-inflammatory cytokine storm, cytopenia, coagulopathy, and multi-organ system dysfunction. MAS can occur in association with infections (herpes viruses), cancer (leukemia), immune deficient states (post-transplantation), and in autoimmune (systemic lupus erythematosus) and autoinflammatory conditions (systemic juvenile idiopathic arthritis). The distinction between fHLH, the result of homozygous defects in cytolytic pathway genes, and MAS is becoming blurred with the identification of single or multiple mutations in the same cytolytic pathway genes in patients with later onset MAS. Here, we review the literature and present novel cytolytic pathway gene mutations identified in children with MAS. We study the inhibitory effect of one these novel mutations on NK cell function to suggest a direct link between fHLH and MAS.
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Macrophage Activation syndrome: advances towards understanding pathogenesis
Current opinion in rheumatology, 2010Co-Authors: Alexei A. GromAbstract:Purpose of review Macrophage Activation syndrome (MAS), a major cause of morbidity and mortality in pediatric rheumatology, is most strongly associated with systemic juvenile idiopathic arthritis (SJIA). There are no validated diagnostic criteria and early diagnosis is difficult. This review summarizes the progress in understanding of MAS pathophysiology that may help define specific diagnostic biomarkers.
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Macrophage Activation syndrome and reactive hemophagocytic lymphohistiocytosis: the same entities?
Current opinion in rheumatology, 2003Co-Authors: Alexei A. GromAbstract:Purpose of the review One of the most perplexing features of systemic-onset juvenile rheumatoid arthritis is the association with Macrophage Activation syndrome, a life-threatening complication caused by excessive Activation and proliferation of T cells and Macrophages. The main purpose of the review is to summarize current understanding of the relation between Macrophage Activation syndrome and other clinically similar hemophagocytic disorders. Recent findings Clinically, Macrophage Activation syndrome has strong similarities with familial and virus-associated reactive hemophagocytic lymphohistiocytosis. The better understood familial hemophagocytic lymphohistiocytosis is a constellation of rare, autosomal recessive immune disorders. The most consistent immunologic abnormalities in patients with familial hemophagocytic lymphohistiocytosis are decreased natural killer and cytotoxic cell functions. In approximately one third of familial hemophagocytic lymphohistiocytosis patients, these immunologic abnormalities are secondary to mutations in the gene encoding perforin, a protein that mediates cytotoxic activity of natural killer and cytotoxic CD8 + T cells. Several recent studies have suggested that profoundly depressed natural killer cell activity and abnormal levels of perforin expression may be a feature of Macrophage Activation syndrome in systemic-onset juvenile rheumatoid arthritis as well. Although it has been proposed that in both hemophagocytic lymphohistiocytosis and Macrophage Activation syndrome, natural killer and cytotoxic cell dysfunction may lead to inadequate control of cellular immune responses, the exact nature of such dysregulation and the relation between Macrophage Activation syndrome and hemophagocytic lymphohistiocytosis still remain to be determined.
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Etanercept in the treatment of Macrophage Activation syndrome.
The Journal of rheumatology, 2001Co-Authors: Sampath Prahalad, Kevin E. Bove, David Dickens, Daniel J. Lovell, Alexei A. GromAbstract:Macrophage Activation syndrome (MAS), a recognized complication of systemic juvenile rheumatoid arthritis (sJRA), has been associated with significant morbidity and mortality. Dysregulation of Macrophage-lymphocyte interactions leading to uncontrolled proliferation of highly activated Macrophages and massive release of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) appears to be central to the pathogenesis of this syndrome. Until now the mainstay of therapy has been corticosteroids and cyclosporin A. We describe a patient with MAS and sJRA successfully treated with the anti-TNF agent etanercept. The outcome in this patient suggests etanercept might be an effective therapeutic agent in MAS.
Lionel B Ivashkiv - One of the best experts on this subject based on the ideXlab platform.
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ifn γ selectively suppresses a subset of tlr4 activated genes and enhancers to potentiate Macrophage Activation
Nature Communications, 2019Co-Authors: Lionel B Ivashkiv, Kyuho Kang, Mahesh Bachu, Sung Ho Park, Keunsoo Kang, Seyeon Bae, Kyunghyun ParkminAbstract:Activation of Macrophage proinflammatory and antimicrobial phenotypes is regulated by IFN-γ and LPS via synergistic induction of canonical, inflammatory NF-κB target genes. However, whether IFN-γ negatively regulates components of the LPS response, and how this may affect Macrophage Activation, is still unclear. Here we use combined transcriptomic and epigenomic approaches to find that IFN-γ selectively abrogates LPS-induced feedback and alters Macrophage metabolic pathways by suppressing TLR4-mediated gene Activation. In contrast to superinduction of inflammatory genes via enhancers that bind IRF1 and STAT1, IFN-γ represses target enhancers that bind STAT3. TLR4-activated but IFN-γ-suppressed enhancers comprise two subsets discernable by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin. Our findings thus show that IFN-γ suppresses feedback inhibitory and metabolic components of TLR responses to enhance Macrophage Activation; they also provide insights for IFN-γ-mediated selective inhibition of TLR4-induced transcription. Such inhibition can contribute to severe and sustained inflammatory responses.
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Macrophage Activation and polarization nomenclature and experimental guidelines
Immunity, 2014Co-Authors: Peter J Murray, Subhra K. Biswas, Judith E Allen, Lionel B Ivashkiv, Edward A. Fisher, Derek W Gilroy, Sergij Goerdt, Siamon Gordon, John A Hamilton, Toby LawrenceAbstract:Description of Macrophage Activation is currently contentious and confusing. Like the biblical Tower of Babel, Macrophage Activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define Macrophage Activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated Macrophages, often termed M1 and M2. Here, we describe a set of standards encompassing three principles—the source of Macrophages, definition of the activators, and a consensus collection of markers to describe Macrophage Activation—with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for Macrophage-Activation nomenclature.
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regulation of interferon and toll like receptor signaling during Macrophage Activation by opposing feedforward and feedback inhibition mechanisms
Immunological Reviews, 2008Co-Authors: Soumya D Chakravarty, Lionel B IvashkivAbstract:Activated Macrophages and their inflammatory products play a key role in innate immunity and in pathogenesis of autoimmune/inflammatory diseases. Macrophage Activation needs to be tightly regulated to rapidly mount responses to infectious challenges but to avoid toxicity associated with excessive Activation. Rapid and potent Macrophage Activation is driven by cytokine-mediated feedforward loops, while excessive Activation is prevented by feedback inhibition. Here we discuss feedforward mechanisms that augment Macrophage responses to Toll-like receptor (TLR) ligands and cytokines that are mediated by signal transducer and activator of transcription 1 (STAT1) and induced by interferon-γ (IFN-γ). IFN-γ also drives full Macrophage Activation by inactivating feedback inhibitory mechanisms, such as those mediated by IL-10 and STAT3. Priming of Macrophages with IFN-γ reprograms cellular responses to other cytokines, such as type I IFNs and IL-10, with a shift toward pro-inflammatory STAT1-dominated responses. Similar but partially distinct priming effects are induced by other cytokines that activate STAT1, including type I IFNs and interleukin-27. We propose a model whereby opposing feedforward and feedback inhibition loops crossregulate each other to fine tune Macrophage Activation. In addition, we discuss how dysregulation of the balance between feedforward and feedback inhibitory mechanisms can contribute to the pathogenesis of autoimmune and inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus.
