scholarly journals Line-selective macrophage activation with an anti-CD40 antibody drives a hemophagocytic syndrome in mice

2020 ◽  
Vol 4 (12) ◽  
pp. 2751-2761
Author(s):  
Giada Ingoglia ◽  
Ayla Yalamanoglu ◽  
Marc Pfefferlé ◽  
Irina L. Dubach ◽  
Christian A. Schaer ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Hemophagocytic Syndrome ◽  
Endothelial Activation ◽  
Interferon Γ ◽  
Multiple Organ ◽  
Preclinical Model ◽  
Cytokine Storm ◽  
Cd40 Gene ◽  
Pathophysiological Role ◽  
Factor Α

Abstract Hemophagocytic syndromes comprise a cluster of hyperinflammatory disorders, including hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Overwhelming macrophage activation has long been considered a final common pathway in the pathophysiology of hemophagocytic syndromes leading to the characteristic cytokine storm, laboratory abnormalities, and organ injuries that define the clinical spectrum of the disease. So far, it is unknown whether primary macrophage activation alone can induce the disease phenotype. In this study, we established a novel mouse model of a hemophagocytic syndrome by treating mice with an agonistic anti-CD40 antibody (Ab). The response in wild-type mice is characterized by a cytokine storm, associated with hyperferritinemia, high soluble CD25, erythrophagocytosis, secondary endothelial activation with multiple organ vaso-occlusion, necrotizing hepatitis, and variable cytopenias. The disease is dependent on a tumor necrosis factor-α–interferon-γ–driven amplification loop. After macrophage depletion with clodronate liposomes or in mice with a macrophage-selective deletion of the CD40 gene (CD40flox/flox/LysMCre), the disease was abolished. These data provide a new preclinical model of a hemophagocytic syndrome and reinforce the key pathophysiological role of macrophages.

Cytokine Profiles of Macrophage Activation Syndrome Associated with Rheumatic Diseases

2010 ◽  
Vol 37 (5) ◽  
pp. 967-973 ◽  
Author(s):  
JUNKO MARUYAMA ◽  
SHIGEKO INOKUMA
Keyword(s):  
Rheumatic Diseases ◽  
Lupus Erythematosus ◽  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Laboratory Data ◽  
Serum Levels ◽  
Interferon Γ ◽  
Cytokine Profiles ◽  
Factor Α ◽  
Activation Syndrome

Objective.To elucidate the cytokine profiles of macrophage activation syndrome (MAS) in relation to underlying rheumatic diseases and prognosis.Methods.The clinical features and laboratory data of 18 patients with MAS and rheumatic diseases were retrospectively analyzed. Serum levels of macrophage colony-stimulating factor (M-CSF), interleukin 18 (IL-18), tumor necrosis factor-α, interleukin 6, interferon-γ, ferritin, and ß2-microglobulin (ß2m) were measured. These data were compared between underlying diseases and between those who died and those who recovered.Results.Of the 18 patients with MAS, 9 had underlying systemic lupus erythematosus (SLE), 7 had adult-onset Still’s disease (AOSD), 1 had rheumatoid arthritis (RA), and 1 had antiphospholipid syndrome. Three patients with SLE and 1 patient with RA died. The serum M-CSF and IL-18 levels were substantially elevated in all the patients. In the patients with SLE, the M-CSF level was higher than the IL-18 level (median: 4879 vs 1341 pg/ml, p = 0.0054), and it was the reverse in the patients with AOSD (5883 vs 228,350 pg/ml, p = 0.0017). The serum M-CSF and ß2m levels were significantly higher in the patients who died than in those who recovered (M-CSF: 18,245 vs 3404 pg/ml, p = 0.019; ß2m: 18.8 vs 5.4 mg/dl, p = 0.0058).Conclusion.The cytokine profiles associated with MAS differed between patients with SLE and patients with AOSD. The patients with SLE showed a prominent increase in serum M-CSF levels, as did the patients with AOSD in serum IL-18 level. Patients who died had higher serum M-CSF and ß2m levels, and this suggests that aggressive treatment for patients with MAS and these profiles should be promptly started.

scholarly journals Cytokine storm in a mouse model of IgG-mediated hemolytic transfusion reactions

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 891-894 ◽  
Author(s):  
Eldad A. Hod ◽  
Chantel M. Cadwell ◽  
Justine S. Liepkalns ◽  
James C. Zimring ◽  
Set A. Sokol ◽  
...  
Keyword(s):  
Mouse Model ◽  
Interferon Γ ◽  
High Plasma ◽  
Cytokine Storm ◽  
Monocyte Chemoattractant Protein 1 ◽  
Tnf Α ◽  
Rapid Clearance ◽  
Factor Α ◽  
Transfusion Reactions

AbstractCytokines are hypothesized to play a central role in the pathophysiology of IgG-mediated hemolytic transfusion reactions (HTRs), and deeper understanding is required for improving therapy for these events. After establishing well-defined mouse models of HTRs, we tested whether cytokines were involved. Red blood cells (RBCs) from human glycophorin A transgenic (hGPA-Tg) or wild-type (WT) mice were transfused into non-Tg recipients passively immunized with monoclonal antibodies (Mabs). Only transfusions of incompatible RBCs induced IgG-mediated HTRs, exemplified by rapid clearance and hemoglobinuria. Very high plasma levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6), and lower levels of tumor necrosis factor-α (TNF-α), were induced after incompatible transfusion. No significant changes in IL-10, IL-12, or interferon-γ (IFN-γ) levels were observed. The proinflammatory cytokines elaborated in this in vivo mouse model are also implicated in the systemic inflammatory response syndrome (SIRS) and confirm the hypothesis that cytokine storm occurs as a result of HTRs.

Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-γ-producing lymphocytes and IL-6- and TNF-α-producing macrophages

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1648-1651 ◽  
Author(s):  
An D. Billiau ◽  
Tania Roskams ◽  
Rita Van Damme-Lombaerts ◽  
Patrick Matthys ◽  
Carine Wouters
Keyword(s):  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Interferon Γ ◽  
Effector Pathway ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Necrosis Factor ◽  
Activation Syndrome

Abstract Macrophage activation syndrome (MAS) is a rare and potentially fatal disorder, thought to result from uncontrolled activation and proliferation of T cells and excessive activation of macrophages. The term MAS designates a clinicopathologic entity that occurs in different hemophagocytic syndromes (HSs). Primary hemophagocytic lymphohistiocytosis (HLH) is recognized to have an immunogenetic basis, but in the secondary HS (also referred to as secondary HLH), the cause is unknown. The pathogenesis of the accelerated disease phase typical of MAS remains incompletely understood. This report describes the immunohistochemical findings on liver tissues from 5 children, each of whom presented with MAS in the context of a different type of HS. The data provide direct evidence for the involvement of activated CD8+ lymphocytes through the production of interferon-γ and of macrophages through hemophagocytosis and production of interleukin 6 and tumor necrosis factor-α, and underscore the view that MAS in different HSs share a common effector pathway. (Blood. 2005;105:1648-1651)

scholarly journals Attenuation of COVID-19-induced cytokine storm in a young male patient with severe respiratory and neurological symptoms

2021 ◽  
Author(s):  
Christian Muschitz ◽  
Anita Trummert ◽  
Theresa Berent ◽  
Norbert Laimer ◽  
Lukas Knoblich ◽  
...  
Keyword(s):  
Decision Making ◽  
Male Patient ◽  
Young Male ◽  
Standard Of Care ◽  
Multiple Organ ◽  
Cytokine Storm ◽  
Invasive Ventilation ◽  
Organ Systems ◽  
The Central Nervous System

SummarySevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), produces protean manifestations and causes indiscriminate havoc in multiple organ systems. This rapid and vast production of proinflammatory cytokines contributes to a condition termed cytokine storm. A 35-year-old, otherwise healthy, employed, male patient was tested positive for COVID-19. He was admitted to the hospital on disease day 10 due to retarded verbal reactions and progressive delirium. On account of these conditions and the need for noninvasive/invasive ventilation, a combination treatment with baricitinib and remdesivir in conjunction with standard of care was initiated. The cytokine storm was rapidly blocked, leading to a vast pulmonary recovery with retarded recovery of the central nervous system. We conclude that the rapid blockade of the COVID-19-induced cytokine storm should be considered of avail as a principle of careful decision-making for effective recovery.

scholarly journals AB0660 COVID-19 SHARES CLINICAL FEATURES WITH ANTI-MELANOMA DIFFERENTIATION ASSOCIATED PROTEIN 5 POSITIVE DERMATOMYOSITIS AND ADULT STILL’S DISEASE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1362.1-1362
Author(s):  
Y. Kondo ◽  
Y. Kaneko ◽  
H. Takei ◽  
H. Tamai ◽  
T. Takeuchi
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Clinical Features ◽  
Serum Ferritin ◽  
Rheumatic Diseases ◽  
Macrophage Activation ◽  
Cytokine Storm ◽  
Still’S Disease ◽  
Still's Disease ◽  
Adult Still's Disease

Background:The coronavirus disease 2019 (COVID-19), caused by a novel corona virus named SARS-CoV-2, has emerged as a global pandemic. Severe inflammatory process is one of main pathogenesis of COVID-19 and this involves cytokine storm along with overactivation of macrophage. On another front, cytokine storm with macrophage activation is frequently observed in various connective tissue diseases including dermatomyositis with positive antimelanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies and adult Still’s disease. Macrophage activation during inflammatory states is partially characterized by an increased serum ferritin levels and hyperferritinaemia and characteristics shared by the three diseases are a topic of interest to rheumatologists, however, no study has evaluated anti-MDA5-positive dermatomyositis and adult Still’s disease in comparison to COVID-19.Objectives:The aim of this study was to highlight the homology and heterogeneity of COVID-19, anti-MDA5 dermatomyositis, and adult Still’s disease by comparing clinical pictures of each disease in order to discuss their respective pathogeneses.Methods:We reviewed consecutive, newly diagnosed, untreated patients with COVID-19, anti-MDA5 dermatomyositis, or adult Still’s disease. We compared their clinical, laboratory, and radiological characteristics, including the prevalence of macrophage activation syndrome and lung involvement in each disease.Results:The numbers of patients with COVID-19, anti-MDA5 dermatomyositis, and adult-onset Still’s disease with hyperferritinaemia (serum ferritin ≥ 500ng/dL) who were included for main analysis were 22, 14, and 59, respectively. COVID-19 and adult Still’s disease both featured hyperinflammatory status, such as high fever and elevated serum C-reactive protein, whereas COVID-19 and anti-MDA5 dermatomyositis both presented with severe interstitial lung disease and hypoxaemia. While two-thirds of the patients in each group met the criteria for macrophage-activated syndrome that is used in systemic juvenile idiopathic arthritis, the HScore, an indicator of haemophagocytic lymphohistiocytosis, was low in anti-MDA5 dermatomyositis and COVID-19 even in severe or critical cases. The findings of chest computed tomography were similar between COVID-19 and anti-MDA5 dermatomyositis (Figure 1).Conclusion:COVID-19 shared clinical features with rheumatic diseases characterised by hyperferritinaemia, including anti-MDA5 dermatomyositis and adult Still’s disease. These findings should be investigated further in order to shed light on the pathogenesis of not only COVID-19 but also the aforementioned rheumatic diseases.References:[1]Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. (2020) 395: 1033-4.[2]Gono T, Sato S, Kawaguchi Y, et al. Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis. Rheumatology (Oxford). 2012; 51(9):1563-70.Figure 1.Imaging characteristics of chest CT scans in patients with COVID-19, anti-MDA5 dermatomyositis, and adult Still’s disease A)Bilateral ground-glass and consolidative opacities with peripheral distribution in COVID-19. B)Bilateral ground-glass opacities with peripheral consolidations in anti-MDA5 dermatomyositis. C)Pleural effusion with pleural thickening on the left side in adult Still’s disease.Disclosure of Interests:Yasushi Kondo: None declared., Yuko Kaneko: None declared., Hisoshi Takei: None declared., Hiroya Tamai: None declared., Tsutomu Takeuchi Grant/research support from: received research grants outside the submitted work from Abbvie, Astra Zeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai Pharmaceutical, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Novartis, Takeda Pharmaceutical, Abbott Japan Co., Ltd., Astellas Pharma, Ltd., Daiichi Sankyo, Pfizer, Sanofi–Aventis, Santen Pharmaceutical, Teijin Pharma Ltd., Asahikasei Pharma Corp., SymBio Pharmaceuticals Ltd., Celtrion, Nipponkayaku Co. Ltd., Eli Lilly Japan, and Taisho Toyama Pharmaceutical.

scholarly journals Pathogenesis and Management of COVID-19

2021 ◽  
Vol 11 (2) ◽  
pp. 77-93
Author(s):  
Khalid O. Alfarouk ◽  
Sari T. S. AlHoufie ◽  
Samrein B. M. Ahmed ◽  
Mona Shabana ◽  
Ahmed Ahmed ◽  
...  
Keyword(s):  
Multiple Organ Failure ◽  
Human Body ◽  
Inflammatory Mediators ◽  
Expression Patterns ◽  
Multiple Organ ◽  
Cytokine Storm ◽  
Chain Reaction ◽  
Road Map ◽  
A Chain ◽  
Global War

COVID-19, occurring due to SARS-COV-2 infection, is the most recent pandemic disease that has led to three million deaths at the time of writing. A great deal of effort has been directed towards altering the virus trajectory and/or managing the interactions of the virus with its subsequent targets in the human body; these interactions can lead to a chain reaction-like state manifested by a cytokine storm and progress to multiple organ failure. During cytokine storms the ratio of pro-inflammatory to anti-inflammatory mediators is generally increased, which contributes to the instigation of hyper-inflammation and confers advantages to the virus. Because cytokine expression patterns fluctuate from one person to another and even within the same person from one time to another, we suggest a road map of COVID-19 management using an individual approach instead of focusing on the blockbuster process (one treatment for most people, if not all). Here, we highlight the biology of the virus, study the interaction between the virus and humans, and present potential pharmacological and non-pharmacological modulators that might contribute to the global war against SARS-COV-2. We suggest an algorithmic roadmap to manage COVID-19.

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