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1.
mBio ; 12(3): e0089921, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34060329

RESUMO

One of the defining features of Staphylococcus aureus is its ability to evade and impair the human immune response through expression of staphylococcal protein A (SpA). Herein, we describe a previously unknown mechanism by which SpA can form toxic immune complexes when in the presence of human serum, which leads to the loss of human leukocytes. Further, we demonstrate that these toxic complexes are formed specifically through SpA's interaction with intact human IgG and that, in the presence of purified IgG Fab and Fc fragments, SpA shows no such toxicity. The mechanism of action of this toxicity appears to be one mediated by necrosis and not by apoptosis, as previously hypothesized, with up to 90% of human B cells rapidly becoming necrotic following stimulation with SpA-IgG complexes. This phenomenon depends on the immunoglobulin binding capacity of SpA, as a nonbinding mutant of SpA did not induce necrosis. Importantly, immune sera raised against SpA had the capacity to significantly reduce the observed toxicity. An unprecedented toxic effect of SpA-IgG complexes on monocytes was also observed, suggesting the existence of a novel mechanism independent from the interaction of SpA with the B cell receptor. Together, these data implicate SpA in inducing indiscriminate leukocyte toxicity upon formation of complexes with IgG and highlight the requirement for vaccination strategies to inhibit this mechanism. IMPORTANCE Staphylococcus aureus is one of the largest health care threats faced by humankind, with a reported mortality rate within the United States greater than that of HIV/AIDS, tuberculosis, and viral hepatitis combined. One of the defining features of S. aureus as a human pathogen is its ability to evade and impair the human immune response through expression of staphylococcal protein A. Herein, we show that SpA induces necrosis in various immune cells by complexing with human immunoglobulins. Vaccination of mice with a nontoxigenic SpA mutant induced sera capable of inhibiting this mechanism. These observations shed new light on the toxic mechanisms of this key staphylococcal virulence factor and on protective modalities of SpA-based vaccination.


Assuntos
Complexo Antígeno-Anticorpo , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Imunoglobulina G/metabolismo , Necrose/imunologia , Proteína Estafilocócica A/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína Estafilocócica A/administração & dosagem , Proteína Estafilocócica A/imunologia , Staphylococcus aureus/metabolismo , Vacinação
2.
Isr Med Assoc J ; 23(6): 373-375, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34155851

RESUMO

BACKGROUND: Surgical interventions in patients with systemic sclerosis (SSc), in particular plastic procedures, might cause undesired consequences. Notably, liposuction seems to possess greater risk as adipose tissue has been shown to play an important role in treating wounds and ulcers in patients with SSc. While anticentromere antibodies were found to be correlated with vasculopathy in SSc, patients with SSc and anticentromere antibodies might be more vulnerable to surgical wound complications following liposuction. A 46-year-old female patient, who had been diagnosed with SSc at the age of 31 years, had antinuclear as well as anticentromere antibodies. She underwent abdominoplasty with liposuction and developed severe skin necrosis of the abdomen following the procedure and at the site of liposuction. The correlation with anticentromere and the role of liposuction in skin necrosis in SSc are presented.


Assuntos
Abdominoplastia , Tecido Adiposo/imunologia , Obesidade Abdominal/cirurgia , Escleroderma Sistêmico , Pele/patologia , Deiscência da Ferida Operatória , Abdominoplastia/efeitos adversos , Abdominoplastia/métodos , Anticorpos Antinucleares/sangue , Cicatriz/diagnóstico , Cicatriz/etiologia , Contraindicações de Procedimentos , Feminino , Humanos , Lipectomia/efeitos adversos , Lipectomia/métodos , Pessoa de Meia-Idade , Necrose/etiologia , Necrose/imunologia , Necrose/cirurgia , Obesidade Abdominal/complicações , Obesidade Abdominal/diagnóstico , Reoperação/efeitos adversos , Reoperação/métodos , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/cirurgia , Cirurgia Plástica/efeitos adversos , Cirurgia Plástica/métodos , Deiscência da Ferida Operatória/diagnóstico , Deiscência da Ferida Operatória/etiologia , Deiscência da Ferida Operatória/cirurgia , Resultado do Tratamento
3.
Annu Rev Phytopathol ; 59: 213-237, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-33945695

RESUMO

Hybrid necrosis in plants refers to a genetic autoimmunity syndrome in the progeny of interspecific or intraspecific crosses. Although the phenomenon was first documented in 1920, it has been unequivocally linked to autoimmunity only recently, with the discovery of the underlying genetic and biochemical mechanisms. The most common causal loci encode immune receptors, which are known to differ within and between species. One mechanism can be explained by the guard hypothesis, in which a guard protein, often a nucleotide-binding site-leucine-rich repeat protein, is activated by interaction with a plant protein that mimics standard guardees modified by pathogen effector proteins. Another surprising mechanism is the formation of inappropriately active immune receptor complexes. In this review, we summarize our current knowledge of hybrid necrosis and discuss how its study is not only informing the understanding of immune gene evolution but also revealing new aspects of plant immune signaling.


Assuntos
Necrose , Doenças das Plantas , Imunidade Vegetal , Evolução Biológica , Interações Hospedeiro-Patógeno , Necrose/imunologia , Doenças das Plantas/imunologia , Proteínas de Plantas , Plantas
4.
Front Immunol ; 12: 631821, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746968

RESUMO

Neutrophils or polymorphonuclear leukocytes (PMN) are key participants in the innate immune response for their ability to execute different effector functions. These cells express a vast array of membrane receptors that allow them to recognize and eliminate infectious agents effectively and respond appropriately to microenvironmental stimuli that regulate neutrophil functions, such as activation, migration, generation of reactive oxygen species, formation of neutrophil extracellular traps, and mediator secretion, among others. Currently, it has been realized that activated neutrophils can accomplish their effector functions and simultaneously activate mechanisms of cell death in response to different intracellular or extracellular factors. Although several studies have revealed similarities between the mechanisms of cell death of neutrophils and other cell types, neutrophils have distinctive properties, such as a high production of reactive oxygen species (ROS) and nitrogen species (RNS), that are important for their effector function in infections and pathologies such as cancer, autoimmune diseases, and immunodeficiencies, influencing their cell death mechanisms. The present work offers a synthesis of the conditions and molecules implicated in the regulation and activation of the processes of neutrophil death: apoptosis, autophagy, pyroptosis, necroptosis, NETosis, and necrosis. This information allows to understand the duality encountered by PMNs upon activation. The effector functions are carried out to eliminate invading pathogens, but in several instances, these functions involve activation of signaling cascades that culminate in the death of the neutrophil. This process guarantees the correct elimination of pathogenic agents, damaged or senescent cells, and the timely resolution of the inflammation that is essential for the maintenance of homeostasis in the organism. In addition, they alert the organism when the immunological system is being deregulated, promoting the activation of other cells of the immune system, such as B and T lymphocytes, which produce cytokines that potentiate the microbicide functions.


Assuntos
Morte Celular/imunologia , Neutrófilos/patologia , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/imunologia , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Radicais Livres/metabolismo , Humanos , Necroptose/imunologia , Necrose/imunologia , Necrose/metabolismo , Ativação de Neutrófilo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fagocitose/imunologia , Piroptose/imunologia , Receptores de Morte Celular/metabolismo
6.
BMJ Case Rep ; 14(1)2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33408110

RESUMO

A 10-year-old boy underwent stem cell transplant for Hodgkin's lymphoma and developed vomiting and seizure in the postoperative period. An ophthalmic referral was made from intensive care unit, to rule out papilledema. On examination, there was no papilledema in both eyes, instead there were areas of retinal necrosis with no haemorrhages or vitritis in right eye. Cerebrospinal fluid serology was negative for herpes but MRI showed hyperintensity in temporal lobe. A clinical diagnosis of progressive outer retinal necrosis (PORN) was made and fundus picture was documented with help of a smartphone and 20D lens. High-dose intravenous injection acyclovir was started and PORN lesion improved on treatment.


Assuntos
Antivirais/administração & dosagem , Transplante de Medula Óssea/efeitos adversos , Infecções por Herpesviridae/diagnóstico , Doença de Hodgkin/terapia , Retina/patologia , Retinite/diagnóstico , Aciclovir/administração & dosagem , Criança , Diagnóstico Diferencial , Relação Dose-Resposta a Droga , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/imunologia , Doença de Hodgkin/imunologia , Humanos , Imunossupressores/efeitos adversos , Achados Incidentais , Imageamento por Ressonância Magnética , Masculino , Necrose/diagnóstico , Necrose/tratamento farmacológico , Necrose/imunologia , Retina/diagnóstico por imagem , Retina/virologia , Síndrome de Necrose Retiniana Aguda/diagnóstico , Retinite/tratamento farmacológico , Retinite/imunologia , Resultado do Tratamento , Ativação Viral/imunologia
7.
Pediatr Nephrol ; 36(4): 1019-1023, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33495896

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is thought to cause kidney injury via a variety of mechanisms. The most common reported kidney injury following COVID-19 infection is acute tubular injury (ATI); however, the procoagulant state induced by the virus may also damage the kidneys. CASE-DIAGNOSIS/TREATMENT: Herein, we report two cases of acute necrotizing glomerulonephritis (GN) with fibrinoid necrosis in the context of COVID-19 infection. The one with more chronic features in the kidney biopsy progressed to permanent kidney failure but the second one had an excellent response to glucocorticoid pulse therapy with subsequent normal kidney function at 2-month follow-up. CONCLUSIONS: Both reported cases had an acute presentation of kidney injury with positive nasopharyngeal PCR test for COVID-19. Based on the data review by the researchers, this is the first report of acute necrotizing GN associated with COVID-19 infection.


Assuntos
Injúria Renal Aguda/etiologia , COVID-19/complicações , Glomerulonefrite/etiologia , Glomérulos Renais/patologia , SARS-CoV-2/patogenicidade , Injúria Renal Aguda/patologia , Injúria Renal Aguda/terapia , Adolescente , Biópsia , Coagulação Sanguínea , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/virologia , Glomerulonefrite/patologia , Glomerulonefrite/terapia , Glucocorticoides/administração & dosagem , Humanos , Glomérulos Renais/irrigação sanguínea , Masculino , Necrose/imunologia , Necrose/patologia , Contagem de Plaquetas , Pulsoterapia , Diálise Renal , SARS-CoV-2/isolamento & purificação , Resultado do Tratamento
8.
Rev Med Virol ; 31(3): e2176, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33022818

RESUMO

The novel coronavirus (SARS-CoV-2) has turned into a life-threatening pandemic disease (Covid-19). About 5% of patients with Covid-19 have severe symptoms including septic shock, acute respiratory distress syndrome, and the failure of several organs, while most of them have mild symptoms. Frequently, the kidneys are involved through direct or indirect mechanisms. Kidney involvement mainly manifests itself as proteinuria and acute kidney injury (AKI). The SARS-CoV-2-induced kidney damage is expected to be multifactorial; directly it can infect the kidney podocytes and proximal tubular cells and based on an angiotensin-converting enzyme 2 (ACE2) pathway it can lead to acute tubular necrosis, protein leakage in Bowman's capsule, collapsing glomerulopathy and mitochondrial impairment. The SARS-CoV-2-driven dysregulation of the immune responses including cytokine storm, macrophage activation syndrome, and lymphopenia can be other causes of the AKI. Organ interactions, endothelial dysfunction, hypercoagulability, rhabdomyolysis, and sepsis are other potential mechanisms of AKI. Moreover, lower oxygen delivery to kidney may cause an ischaemic injury. Understanding the fundamental molecular pathways and pathophysiology of kidney injury and AKI in Covid-19 is necessary to develop management strategies and design effective therapies.


Assuntos
Injúria Renal Aguda/patologia , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/patologia , Coagulação Intravascular Disseminada/patologia , Linfopenia/patologia , Necrose/patologia , Proteinúria/patologia , Sepse/patologia , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/virologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/imunologia , COVID-19/imunologia , COVID-19/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Citocinas/genética , Citocinas/imunologia , Coagulação Intravascular Disseminada/imunologia , Coagulação Intravascular Disseminada/virologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Túbulos Renais Proximais/imunologia , Túbulos Renais Proximais/fisiopatologia , Linfopenia/imunologia , Linfopenia/virologia , Necrose/imunologia , Necrose/virologia , Podócitos/imunologia , Podócitos/patologia , Proteinúria/imunologia , Proteinúria/virologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Sepse/imunologia , Sepse/virologia , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
9.
J Invest Dermatol ; 141(4): 810-820.e8, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32946878

RESUMO

The staphylococcal α-hemolysin is critical for the pathogenesis of Staphylococcus aureus skin and soft tissue infection. Vaccine and infection-elicited α-hemolysin-specific antibodies protect against S. aureus‒induced dermonecrosis, a key feature of skin and soft tissue infection. Many interactions between α-hemolysin and host cells have been identified that promote tissue damage and modulate immune responses, but the mechanisms by which protective adaptive responses cross talk with innate responses at the tissue level are not clear. Using an established mouse model of skin and soft tissue infection and a newly developed histopathologic scoring system, we observed pathologic correlates early after infection, predicting protection against dermonecrosis by anti-α-hemolysin antibody. Protection was characterized by robust neutrophilic inflammation and compartmentalization of bacteria into discrete abscesses, which led to the attenuation of dermonecrosis and enhancement of bacterial clearance later in the infection. The ultimate outcome of infection was driven by the recruitment of neutrophils within the first day after infection but not later. Antibody-mediated protection was dependent on toxin neutralization rather than on enhanced opsonophagocytic killing by neutrophils or protection against toxin-mediated neutrophil lysis. Together, these findings advance our understanding of the mechanisms by which the early synergism between antibody-mediated toxin neutralization and tissue-specific neutrophilic inflammation preserve tissue integrity during infection.


Assuntos
Anticorpos Antibacterianos/metabolismo , Anticorpos Neutralizantes/metabolismo , Toxinas Bacterianas/imunologia , Proteínas Hemolisinas/imunologia , Neutrófilos/imunologia , Pele/patologia , Infecções Cutâneas Estafilocócicas/imunologia , Animais , Anticorpos Antibacterianos/administração & dosagem , Anticorpos Antibacterianos/imunologia , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Feminino , Voluntários Saudáveis , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/metabolismo , Humanos , Imunização Passiva/métodos , Camundongos , Necrose/imunologia , Necrose/microbiologia , Necrose/patologia , Infiltração de Neutrófilos , Cultura Primária de Células , Pele/imunologia , Pele/microbiologia , Infecções Cutâneas Estafilocócicas/microbiologia , Infecções Cutâneas Estafilocócicas/patologia , Staphylococcus aureus/imunologia
10.
Rheumatology (Oxford) ; 60(6): 2916-2926, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-33249503

RESUMO

OBJECTIVE: The aim of our study was to investigate clinical and histopathological findings in adult DM patients positive for anti-Mi2 (anti-Mi2+) antibodies compared with DM patients negative for anti-Mi2 (anti-Mi2-). METHODS: Clinical data of adult DM patients, who fulfilled EULAR/ACR 2017 classification criteria, were gathered from electronic medical records of three tertiary Rheumatology Units. Histopathological study was carried out on 12 anti-Mi2+ and 14 anti-Mi2- muscle biopsies performed for diagnostic purpose. Nine biopsies from immune mediated necrotizing myopathy (IMNM) patients were used as control group. RESULTS: Twenty-two anti-Mi2+ DM [90.9% female, mean age 56.5 (15.7) years] were compared with 69 anti-Mi2- DM patients [71% female, mean age 52.4 (17) years]. Anti-Mi2+ patients presented higher levels of serum muscle enzymes than anti-Mi2- patients [median (IQR) creatine-kinase fold increment: 16 (7-37)vs 3.5 (1-9.9), P <0.001] before treatment initiation. Moreover, a trend towards less pulmonary involvement was detected in anti-Mi2+ DM (9.1% vs 30.4%, P =0.05), without any case of rapidly progressive interstitial lung disease. At muscle histology, anti-Mi2+ patients showed more necrotic/degenerative fibres than anti-Mi2- patients [mean 5.3% (5) vs 0.8% (1), P <0.01], but similar to IMNM [5.9% (6), P >0.05]. In addition, the endomysial macrophage score was similar between anti-Mi2+ and IMNM patients [mean 1.2 (0.9) vs 1.3 (0.5), P >0.05], whereas lower macrophage infiltration was found in anti-Mi2- DM [mean 0.4 (0.5), <0.01]. CONCLUSIONS: Anti-Mi2+ patients represent a specific DM subset with high muscle damage. Histological hallmarks were a higher prevalence of myofiber necrosis, endomysial involvement and macrophage infiltrates at muscle biopsy.


Assuntos
Autoanticorpos/imunologia , Dermatomiosite/imunologia , Necrose/imunologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Macrófagos/imunologia , Masculino , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/imunologia , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
Fish Shellfish Immunol ; 108: 73-79, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33285163

RESUMO

A unique strain of Vibrio harveyi is the causative agent of scale drop and muscle necrosis disease (SDMND) in Asian sea bass (Lates calcarifer). This study investigated the protein profiles of SDMND-causing Vibrio harveyi isolates compared to the reference V. harveyi ATCC 14126 strain. A distinct protein band of 33 kDa, namely HP33, found from only V. harveyi SDMND was subjected to analysis by LC-MS/MS and the identified peptide sequences matched to an unknown hypothetical protein. Detection of HP33 coding sequence was investigated at both genomic and transcriptional levels and the results consistently supported the protein analysis. Recombinant HP33 protein was then produced using Escherichia coli system. The rHP33 protein did not cause mortality or visible clinical signs to Asian sea bass. However, the rHP33 protein was able to stimulate antibody response in Asian sea bass as evidenced by Western blotting and agglutination tests. Here, we proposed that rHP33 might be a good protein target for development of subunit vaccine and/or immunostimulant to protect Asian sea bass from SDMND.


Assuntos
Proteínas de Bactérias/genética , Bass , Doenças dos Peixes/imunologia , Imunogenicidade da Vacina , Necrose/veterinária , Vibrioses/veterinária , Vibrio/imunologia , Escamas de Animais/patologia , Animais , Proteínas de Bactérias/imunologia , Doenças dos Peixes/microbiologia , Doenças Musculares/imunologia , Doenças Musculares/microbiologia , Doenças Musculares/veterinária , Necrose/imunologia , Necrose/microbiologia , Vibrio/genética , Vibrioses/imunologia , Vibrioses/microbiologia
12.
J Leukoc Biol ; 110(2): 343-356, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33205451

RESUMO

Treatment of solid tumors is often hindered by an immunosuppressive tumor microenvironment (TME) that prevents effector immune cells from eradicating tumor cells and promotes tumor progression, angiogenesis, and metastasis. Therefore, targeting components of the TME to restore the ability of immune cells to drive anti-tumoral responses has become an important goal. One option is to induce an immunogenic cell death (ICD) of tumor cells that would trigger an adaptive anti-tumoral immune response. Here we show that incubating mouse renal cell carcinoma (RENCA) and colon carcinoma cell lines with an anti-extracellular matrix metalloproteinase inducer polyclonal antibody (161-pAb) together with complement factors can induce cell death that inhibits caspase-8 activity and enhances the phosphorylation of receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase-like domain (MLKL). This regulated necrotic death releases high levels of dsRNA molecules to the conditioned medium (CM) relative to the necrotic death of tumor cells induced by H2 O2 or the apoptotic death induced by etoposide. RAW 264.7 macrophages incubated with the CM derived from these dying cells markedly enhanced the secretion of IFNß, and enhanced their cytotoxicity. Furthermore, degradation of the dsRNA in the CM abolished the ability of RAW 264.7 macrophages to secrete IFNß, IFNγ-induced protein 10 (IP-10), and TRAIL. When mice bearing RENCA tumors were immunized with the 161-pAb, their lysates displayed elevated levels of phosphorylated RIPK3 and MLKL, as well as increased concentrations of dsRNA, IFNß, IP-10, and TRAIL. This shows that an antigen-targeted therapy using an antibody and complement factors that triggers ICD can shift the mode of macrophage activation by triggering regulated necrotic death of tumor cells.


Assuntos
Basigina/imunologia , Proteínas do Sistema Complemento/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Necrose/imunologia , Trifosfato de Adenosina/metabolismo , Animais , Biomarcadores , Caspases/metabolismo , Sobrevivência Celular , Citotoxicidade Imunológica , DNA de Neoplasias/imunologia , Modelos Animais de Doenças , Humanos , Imunomodulação , L-Lactato Desidrogenase/metabolismo , Camundongos
14.
Am J Respir Cell Mol Biol ; 64(5): 547-556, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33332993

RESUMO

Over the last several decades, our understanding of regulated-cell-death (RCD) pathways has increased dramatically. In addition to apoptosis and accidental cell death (primary necrosis), a diverse spectrum of RCD pathways has been delineated. In the lung, airway macrophages are critical for maintaining the functionality of airways via the clearance of inhaled particles, cell debris, and infectious agents. Exposure of these cells to pathogenic organisms or particles can induce a variety of RCD pathways that promote the release of danger signals into the lung. These responses have evolved to trigger the innate and adaptive arms of the immune system and thus offer protection against pathogens; yet they can also contribute to the development of lung injury and pathogenic immune responses. In this review, we discuss recent studies that suggest a critical role for airway-macrophage RCD pathways in promoting the release of pulmonary danger signals in health and disease.


Assuntos
Alarminas/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Lesão Pulmonar/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Síndrome do Desconforto Respiratório/imunologia , Imunidade Adaptativa , Alarminas/genética , Animais , Apoptose/genética , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/genética , Citocinas/genética , Citocinas/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Pulmão/patologia , Lesão Pulmonar/genética , Lesão Pulmonar/patologia , Macrófagos Alveolares/patologia , Necrose/genética , Necrose/imunologia , Necrose/patologia , Piroptose/genética , Piroptose/imunologia , Síndrome do Desconforto Respiratório/genética , Síndrome do Desconforto Respiratório/patologia , Transdução de Sinais
15.
Nat Commun ; 11(1): 6296, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293558

RESUMO

Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.


Assuntos
ATP Citrato (pro-S)-Liase/deficiência , Macrófagos/metabolismo , Placa Aterosclerótica/imunologia , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , ATP Citrato (pro-S)-Liase/genética , Idoso , Animais , Apoptose/imunologia , Colesterol/biossíntese , Colágeno/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ácidos Graxos/biossíntese , Feminino , Fibrose , Perfilação da Expressão Gênica , Humanos , Lipidômica , Lipogênese/imunologia , Receptores X do Fígado/metabolismo , Ativação de Macrófagos , Macrófagos/imunologia , Masculino , Camundongos Knockout , Necrose/imunologia , Necrose/patologia , Fagocitose , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/patologia
16.
PLoS One ; 15(11): e0239481, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33151930

RESUMO

25-Hydroxyvitamin D [25(OH)D] has been reported to be associated with several chronic liver diseases. The relationship between 25(OH)D and autoimmune hepatitis (AIH) pathogenesis is incompletely understood. We investigated the association of serum total and free 25(OH)D levels with necroinflammatory activity and cytokine levels in 66 patients with AIH diagnosed in our hospital. The median age at AIH diagnosis was 57 years, and the male:female ratio was 7:59. The median serum total 25(OH)D level in therapy-naïve patients with AIH was 14.2 ng/mL (interquartile range [IQR], 11.4-17.9 ng/mL). Of the 66 patients with AIH, 36 had serum total 25(OH)D levels of < 15 ng/mL and were considered to have vitamin D deficiency, and 30 had serum total 25(OH)D levels of ≥ 15 ng/mL. Patients with acute-onset AIH had significantly lower serum total 25(OH)D levels than those with chronic-onset AIH. In particular, serum total 25(OH)D levels were significantly lower in patients with severe forms of AIH. Furthermore, the serum total 25(OH)D level was positively correlated with the serum albumin level and prothrombin time and negatively correlated with the serum total bilirubin level and necroinflammatory activity in AIH. Multivariate logistic regression analysis showed that the serum total 25(OH)D level was an independent factor for severe necroinflammatory activity. Interestingly, AIH patients with serum total 25(OH)D levels of < 15 ng/mL had higher levels of inflammatory cytokines such as interferon-γ and interleukin-33. Free 25(OH)D levels were correlated with total 25(OH)D levels, and the percentage of free 25(OH)D was significantly associated with necroinflammatory activity. In conclusion, 25(OH)D deficiency may play an important role in predicting AIH severity via inflammatory cytokine production.


Assuntos
Citocinas/metabolismo , Hepatite Autoimune/diagnóstico , Fígado/patologia , Deficiência de Vitamina D/imunologia , Vitamina D/análogos & derivados , Estudos de Casos e Controles , Feminino , Hepatite Autoimune/sangue , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Humanos , Fígado/imunologia , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Necrose/sangue , Necrose/diagnóstico , Necrose/imunologia , Necrose/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico
17.
Nat Rev Rheumatol ; 16(12): 689-701, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33093664

RESUMO

Immune-mediated necrotizing myopathy (IMNM) is a group of inflammatory myopathies that was distinguished from polymyositis in 2004. Most IMNMs are associated with anti-signal recognition particle (anti-SRP) or anti-3-hydroxy-3-methylglutaryl-coA reductase (anti-HMGCR) myositis-specific autoantibodies, although ~20% of patients with IMNM remain seronegative. These associations have led to three subclasses of IMNM: anti-SRP-positive IMNM, anti-HMGCR-positive IMNM and seronegative IMNM. IMNMs are frequently rapidly progressive and severe, displaying high serum creatine kinase levels, and failure to treat IMNMs effectively may lead to severe muscle impairment. In patients with seronegative IMNM, disease can be concomitant with cancer. Research into IMNM pathogenesis has shown that anti-SRP and anti-HMGCR autoantibodies cause weakness and myofibre necrosis in mice, suggesting that, as well as being diagnostic biomarkers of IMNM, they may play a key role in disease pathogenesis. Therapeutically, treatments such as rituximab or intravenous immunoglobulins can now be discussed for IMNM, and targeted therapies, such as anticomplement therapeutics, may be a future option for patients with refractory disease.


Assuntos
Doenças Autoimunes/diagnóstico , Músculo Esquelético/patologia , Miosite/diagnóstico , Animais , Anti-Inflamatórios/uso terapêutico , Autoanticorpos/imunologia , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/fisiopatologia , Doenças Autoimunes/terapia , Biópsia , Humanos , Hidroximetilglutaril-CoA Redutases/imunologia , Fatores Imunológicos/uso terapêutico , Camundongos , Músculo Esquelético/imunologia , Miosite/epidemiologia , Miosite/fisiopatologia , Miosite/terapia , Necrose/imunologia , Necrose/patologia , Prognóstico , Partícula de Reconhecimento de Sinal/antagonistas & inibidores , Partícula de Reconhecimento de Sinal/imunologia
18.
Front Immunol ; 11: 1297, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765490

RESUMO

Complement plays an essential role in the opsonophagocytic clearance of apoptotic/necrotic cells. Dysregulation of this process may lead to inflammatory and autoimmune diseases. Factor H (FH), a major soluble complement inhibitor, binds to dead cells and inhibits excessive complement activation on their surface, preventing lysis, and the release of intracellular material, including DNA. The FH-related (FHR) proteins share common ligands with FH, due to their homology with this complement regulator, but they lack the domains that mediate the complement inhibitory activity of FH. Because their roles in complement regulation is controversial and incompletely understood, we studied the interaction of FHR-1 and FHR-5 with DNA and dead cells and investigated whether they influence the regulatory role of FH and the complement activation on DNA and dead cells. FH, FHR-1, and FHR-5 bound to both plasmid DNA and human genomic DNA, where both FHR proteins inhibited FH-DNA interaction. The FH cofactor activity was inhibited by FHR-1 and FHR-5 due to the reduced binding of FH to DNA in the presence of the FHRs. Both FHRs caused increased complement activation on DNA. FHR-1 and FHR-5 bound to late apoptotic and necrotic cells and recruited monomeric C-reactive protein and pentraxin 3, and vice versa. Interactions of the FHRs with pentraxins resulted in enhanced activation of both the classical and the alternative complement pathways on dead cells when exposed to human serum. Altogether, our results demonstrate that FHR-1 and FHR-5 are competitive inhibitors of FH on DNA; moreover, FHR-pentraxin interactions promote opsonization of dead cells.


Assuntos
Proteínas Inativadoras do Complemento C3b/metabolismo , Proteínas do Sistema Complemento/metabolismo , DNA/metabolismo , Apoptose/imunologia , Morte Celular/genética , Morte Celular/imunologia , Linhagem Celular Tumoral , Ativação do Complemento , Proteínas do Sistema Complemento/imunologia , Células Endoteliais , Armadilhas Extracelulares/genética , Armadilhas Extracelulares/imunologia , Citometria de Fluxo , Humanos , Necrose/imunologia , Ligação Proteica
19.
BMC Cancer ; 20(1): 812, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847533

RESUMO

BACKGROUND: Microwave ablation (MWA) is widely used to treat unresectable primary and secondary malignancies of the liver, and a limited number of studies indicate that ablation can cause not only necrosis at the in situ site but also an immunoreaction of the whole body. This study aimed to investigate the effects of MWA on cytokines in patients who underwent MWA for a hepatic malignancy. METHODS: Patients admitted to the Oncology Department in the First Affiliated Hospital of Soochow University between June 2015 and February 2019 were selected. Peripheral blood was collected from patients with a hepatic malignancy treated with MWA. The levels of cytokines (IL-2, IFN-γ, TNF-α, IL-12 p40, IL-12 p70, IL-4, IL-6, IL-8, IL-10, and vascular endothelial growth factor (VEGF)) were detected with a Milliplex® MAP Kit. The comparison times were as follows: before ablation, 24 h after ablation, 15 days after ablation, and 30 days after ablation. Data were analyzed using a paired sample t-tests and Spearman's correlation analysis. RESULTS: A total of 43 patients with hepatic malignancies were assessed. There were significant differences in IL-2, IL-12 p40, IL-12 p70, IL-1ß, IL-8, and TNF-α at 24 h after MWA. Significant increases (> 2-fold vs. before ablation) were observed in IL-2, IL-1ß, IL-6, IL-8, IL-10, and TNF-α after MWA. Elevated IL-2 and IL-6 levels after ablation were positively correlated with energy output during the MWA procedure. CONCLUSIONS: WA treatment for hepatic malignancies can alter the serum levels of several cytokines such as IL-2 and IL-6.


Assuntos
Técnicas de Ablação/efeitos adversos , Interleucina-2/sangue , Interleucina-6/sangue , Neoplasias Hepáticas/cirurgia , Micro-Ondas/efeitos adversos , Técnicas de Ablação/métodos , Idoso , Feminino , Humanos , Interleucina-2/imunologia , Interleucina-6/imunologia , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Necrose/sangue , Necrose/imunologia , Período Pós-Operatório
20.
Front Immunol ; 11: 1267, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655564

RESUMO

Dendritic cells (DCs) play a key role in initiating and regulating the immune responses to pathogens, self-antigens, and cancers. Human blood DCs comprise a family of different subsets: plasmacytoid DCs (pDCs) and CD16+, CD1c/BDCA1+, and BDCA3+ (CD141+) myeloid DCs and possess different phenotypes and functional characteristics. Lung cancer is the most common cancer, with the highest morbidity and mortality in the world. However, which DC subset plays a leading role in the lung cancer immune responses is unclear. We reanalyzed C-type lectin domain family 9 member A (CLEC9A) and CD141 (THBD) gene expression profiles from the Cancer Genome Atlas (TCGA) database and performed the Kaplan-Meier survival analysis of overall survival for several cancers according to their expression levels. Next, we investigated the capacities of five human blood DC subsets to stimulate T cell proliferation and capture, process and (cross-) present tumor antigen. Human BDCA3+ (CD141+) DCs have a superior capacity to stimulate allogeneic CD4+T cells proliferation and induce superior Th1 response compared with other DC subsets. Interestingly, toll-like receptor (TLR) agonists have little effect on DCs to induce the proliferation of naïve CD4+ T cells, but contribute to their differentiation. Importantly, BDCA3+ (CD141+) DCs possess the most potent ability to cross-present human tumor antigen after their uptake of necrotic lung cancer cells despite their lower antigen uptake. These findings suggest that human BDCA3+ (CD141+) DCs are critical mediators of cytotoxic T lymphocyte responses against EGFR-positive lung cancer. Therefore, our findings may provide theoretical basis for the development of DC-based antitumor vaccines.


Assuntos
Antígenos de Neoplasias/imunologia , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos T Citotóxicos/imunologia , Antígenos de Superfície/imunologia , Células Cultivadas , Humanos , Necrose/imunologia
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