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1.
Cancer Cell ; 40(9): 986-998.e5, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-36055226

RESUMO

Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L-/- platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8+ T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD.


Assuntos
Plaquetas/imunologia , Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Receptores Purinérgicos P2Y12/metabolismo , Animais , Ligante de CD40/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética
2.
J Biomed Sci ; 29(1): 52, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35820906

RESUMO

BACKGROUND: Coronavirus-induced disease 19 (COVID-19) infects more than three hundred and sixty million patients worldwide, and people with severe symptoms frequently die of acute respiratory distress syndrome (ARDS). Recent studies indicated that excessive neutrophil extracellular traps (NETs) contributed to immunothrombosis, thereby leading to extensive intravascular coagulopathy and multiple organ dysfunction. Thus, understanding the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced NET formation would be helpful to reduce thrombosis and prevent ARDS in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We incubated SARS-CoV-2 with neutrophils in the presence or absence of platelets to observe NET formation. We further isolated extracellular vesicles from COVID-19 patients' sera (COVID-19-EVs) to examine their ability to induce NET formation. RESULTS: We demonstrated that antagonistic mAbs against anti-CLEC5A mAb and anti-TLR2 mAb can inhibit COVID-19-EVs-induced NET formation, and generated clec5a-/-/tlr2-/- mice to confirm the critical roles of CLEC5A and TLR2 in SARS-CoV-2-induced lung inflammation in vivo. We found that virus-free extracellular COVID-19 EVs induced robust NET formation via Syk-coupled C-type lectin member 5A (CLEC5A) and TLR2. Blockade of CLEC5A inhibited COVID-19 EVs-induced NETosis, and simultaneous blockade of CLEC5A and TLR2 further suppressed SARS-CoV-2-induced NETosis in vitro. Moreover, thromboinflammation was attenuated dramatically in clec5a-/-/tlr2-/- mice. CONCLUSIONS: This study demonstrates that SARS-CoV-2-activated platelets produce EVs to enhance thromboinflammation via CLEC5A and TLR2, and highlight the importance of CLEC5A and TLR2 as therapeutic targets to reduce the risk of ARDS in COVID-19 patients.


Assuntos
COVID-19 , Lectinas Tipo C , Neutrófilos , Pneumonia , Síndrome do Desconforto Respiratório , SARS-CoV-2 , Trombose , Animais , Plaquetas/imunologia , Plaquetas/patologia , Plaquetas/virologia , COVID-19/sangue , COVID-19/imunologia , Humanos , Lectinas Tipo C/imunologia , Camundongos , Neutrófilos/imunologia , Neutrófilos/patologia , Neutrófilos/virologia , Pneumonia/imunologia , Pneumonia/patologia , Pneumonia/virologia , Receptores de Superfície Celular , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/imunologia , Trombose/sangue , Trombose/imunologia , Trombose/virologia , Receptor 2 Toll-Like/imunologia
3.
Front Immunol ; 13: 834988, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35309299

RESUMO

Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease. Platelets are important mediators and sensors of inflammation and are directly affected by cardiovascular stressors. In this report, we found that platelets from severely ill, hospitalized COVID-19 patients exhibited higher basal levels of activation measured by P-selectin surface expression and had poor functional reserve upon in vitro stimulation. To investigate this question in more detail, we developed an assay to assess the capacity of plasma from COVID-19 patients to activate platelets from healthy donors. Platelet activation was a common feature of plasma from COVID-19 patients and correlated with key measures of clinical outcome including kidney and liver injury, and APACHEIII scores. Further, we identified ferritin as a pivotal clinical marker associated with platelet hyperactivation. The COVID-19 plasma-mediated effect on control platelets was highest for patients that subsequently developed inpatient thrombotic events. Proteomic analysis of plasma from COVID-19 patients identified key mediators of inflammation and cardiovascular disease that positively correlated with in vitro platelet activation. Mechanistically, blocking the signaling of the FcγRIIa-Syk and C5a-C5aR pathways on platelets, using antibody-mediated neutralization, IgG depletion or the Syk inhibitor fostamatinib, reversed this hyperactivity driven by COVID-19 plasma and prevented platelet aggregation in endothelial microfluidic chamber conditions. These data identified these potentially actionable pathways as central for platelet activation and/or vascular complications and clinical outcomes in COVID-19 patients. In conclusion, we reveal a key role of platelet-mediated immunothrombosis in COVID-19 and identify distinct, clinically relevant, targetable signaling pathways that mediate this effect.


Assuntos
Plaquetas/imunologia , COVID-19/imunologia , Complemento C5a/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Receptores de IgG/metabolismo , SARS-CoV-2/fisiologia , Tromboembolia/imunologia , Adulto , Aminopiridinas/farmacologia , Células Cultivadas , Feminino , Hospitalização , Humanos , Masculino , Morfolinas/farmacologia , Ativação Plaquetária , Pirimidinas/farmacologia , Índice de Gravidade de Doença , Transdução de Sinais , Quinase Syk/antagonistas & inibidores
4.
BMC Cardiovasc Disord ; 22(1): 45, 2022 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-35152878

RESUMO

BACKGROUND AND AIMS: Inflammation plays a key role in the initiation and progression of atrial fibrillation (AF). The systemic inflammation indexes are easily evaluated and predict AF development. However, it's role in prediction of recurrence of AF is unknown. We aim to explore the association between the systemic inflammation indexes and recurrence of AF in patients underwent cryoablation (CryoMaze) concomitant with mitral valve surgery. METHODS: We examined systemic inflammation indexes during perioperative period in 122 patients between 2015 and 2018. Systemic inflammation indexes were developed by systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocytes to monocytes ratio. Univariate and multivariate analyses were performed to examine the association of each markers with recurrence of AF. RESULTS: Of the 122 patients included in this study, 22 patients (18%) experienced AF recurrence after CryoMaze concomitant with mitral valve surgery. There is no significant difference between each systemic inflammation indexes before surgery and recurrence of AF. In univariate analysis, MLR after surgery 3 days, PLR, MPLR, NLR, SII after surgery 7 days were able to predict recurrence of AF. In multivariate analyses, SII ≥ 1696 independently predicted recurrence (OR, 3.719; 95% CI, 1.417-9.760). Interestingly, baseline SII showed no significant in prediction of recurrence. It was sharply elevated after surgery and dropped slowly. In patients of recurrence, SII after 7 days of surgery increased again. CONCLUSIONS: The raised SII again was associated with an increased risk of the postoperative recurrence of AF and independently predicted the late recurrence of AF after CryoMaze concomitant with mitral valve surgery.


Assuntos
Fibrilação Atrial/cirurgia , Criocirurgia/efeitos adversos , Técnicas de Apoio para a Decisão , Doenças das Valvas Cardíacas/cirurgia , Inflamação/diagnóstico , Procedimento do Labirinto/efeitos adversos , Valva Mitral/cirurgia , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/imunologia , Fibrilação Atrial/fisiopatologia , Plaquetas/imunologia , Feminino , Doenças das Valvas Cardíacas/diagnóstico , Doenças das Valvas Cardíacas/imunologia , Doenças das Valvas Cardíacas/fisiopatologia , Humanos , Inflamação/imunologia , Contagem de Linfócitos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Valva Mitral/fisiopatologia , Monócitos/imunologia , Contagem de Plaquetas , Valor Preditivo dos Testes , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
5.
Front Immunol ; 13: 847894, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35173744

RESUMO

CD39/NTPDase1 has emerged as an important molecule that contributes to maintain inflammatory and coagulatory homeostasis. Various studies have hypothesized the possible role of CD39 in COVID-19 pathophysiology since no confirmatory data shed light in this regard. Therefore, we aimed to quantify CD39 expression on COVID-19 patients exploring its association with severity clinical parameters and ICU admission, while unraveling the role of purinergic signaling on thromboinflammation in COVID-19 patients. We selected a prospective cohort of patients hospitalized due to severe COVID-19 pneumonia (n=75), a historical cohort of Influenza A pneumonia patients (n=18) and sex/age-matched healthy controls (n=30). CD39 was overexpressed in COVID-19 patients' plasma and immune cell subsets and related to hypoxemia. Plasma soluble form of CD39 (sCD39) was related to length of hospital stay and independently associated with intensive care unit admission (adjusted odds ratio 1.04, 95%CI 1.0-1.08, p=0.038), with a net reclassification index of 0.229 (0.118-0.287; p=0.036). COVID-19 patients showed extracellular accumulation of adenosine nucleotides (ATP and ADP), resulting in systemic inflammation and pro-coagulant state, as a consequence of purinergic pathway dysregulation. Interestingly, we found that COVID-19 plasma caused platelet activation, which was successfully blocked by the P2Y12 receptor inhibitor, ticagrelor. Therefore, sCD39 is suggested as a promising biomarker for COVID-19 severity. As a conclusion, our study indicates that CD39 overexpression in COVID-19 patients could be indicating purinergic signaling dysregulation, which might be at the basis of COVID-19 thromboinflammation disorder.


Assuntos
Apirase/sangue , Apirase/metabolismo , COVID-19/patologia , Receptores Purinérgicos P2Y/metabolismo , Tromboinflamação/patologia , Difosfato de Adenosina/análise , Trifosfato de Adenosina/análise , Biomarcadores/sangue , Plaquetas/imunologia , Hipóxia Celular/fisiologia , Cuidados Críticos/estatística & dados numéricos , Feminino , Humanos , Vírus da Influenza A/imunologia , Influenza Humana/patologia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/imunologia , Prognóstico , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/farmacologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Tromboinflamação/imunologia , Ticagrelor/farmacologia
6.
Front Immunol ; 13: 825892, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35185916

RESUMO

Platelets are anucleate cytoplasmic fragments derived from the fragmentation of medullary megakaryocytes. Activated platelets adhere to the damaged endothelium by means of glycoproteins on their surface, forming the platelet plug. Activated platelets can also secrete the contents of their granules, notably the growth factors contained in the α-granules, which are involved in platelet aggregation and maintain endothelial activation, but also contribute to vascular repair and angiogenesis. Platelets also have a major inflammatory and immune function in antibacterial defence, essentially through their Toll-like Receptors (TLRs) and Sialic acid-binding immunoglobulin-type lectin (SIGLEC). Platelet activation also contributes to the extensive release of anti- or pro-inflammatory mediators such as IL-1ß, RANTES (Regulated on Activation, Normal T Expressed and Secreted) or CD154, also known as the CD40-ligand. Platelets are involved in the direct activation of immune cells, polynuclear neutrophils (PNNs) and dendritic cells via the CD40L/CD40 complex. As a general rule, all of the studies presented in this review show that platelets are capable of covering most of the stages of inflammation, primarily through the CD40L/CD40 interaction, thus confirming their own role in this pathophysiological condition.


Assuntos
Plaquetas/imunologia , Antígenos CD40/imunologia , Ligante de CD40/metabolismo , Inflamação/imunologia , Animais , Humanos , Mediadores da Inflamação/metabolismo , Ativação Plaquetária , Transdução de Sinais
7.
Circ Res ; 130(2): 288-308, 2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-35050690

RESUMO

Classically, platelets have been described as the cellular blood component that mediates hemostasis and thrombosis. This important platelet function has received significant research attention for >150 years. The immune cell functions of platelets are much less appreciated. Platelets interact with and activate cells of all branches of immunity in response to pathogen exposures and infection, as well as in response to sterile tissue injury. In this review, we focus on innate immune mechanisms of platelet activation, platelet interactions with innate immune cells, as well as the intersection of platelets and adaptive immunity. The immune potential of platelets is dependent in part on their megakaryocyte precursor providing them with the molecular composition to be first responders and immune sentinels in initiating and orchestrating coordinated pathogen immune responses. There is emerging evidence that extramedullary megakaryocytes may be immune differentiated compared with bone marrow megakaryocytes, but the physiological relevance of immunophenotypic differences are just beginning to be explored. These concepts are also discussed in this review. The immune functions of the megakaryocyte/platelet lineage have likely evolved to coordinate the need to repair a vascular breach with the simultaneous need to induce an immune response that may limit pathogen invasion once the blood is exposed to an external environment.


Assuntos
Imunidade Adaptativa , Plaquetas/imunologia , Imunidade Inata , Megacariócitos/imunologia , Animais , Humanos
8.
Int J Hematol ; 115(3): 322-328, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35037230

RESUMO

Autoimmune hematological disorders are rare complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Diagnosis of immune thrombocytopenia (ITP) is challenging, especially after allo-HSCT, because various complications such as graft-versus-host disease, disease relapse, viral infection, thrombotic microangiopathy, and drug side effects can also cause thrombocytopenia. Assessment of reticulated platelets (RP) and plasma thrombopoietin (TPO) levels may be useful to distinguish between ITP and hypoplastic thrombocytopenia. ITP is generally characterized by an increased percentage of RP, and a normal or slightly increased plasma TPO level. We now report three cases of thrombocytopenia after allo-HSCT. RP% was elevated in these patients, as it is in primary ITP. However, in contrast to primary ITP, plasma TPO levels were high in two of three patients. Anti-αIIbß3 and anti-GPIb/IX-specific direct IgG antibodies were detected as well, suggesting occurrence of immune-mediated platelet destruction in addition to bone marrow suppression in two patients. All three patients were successfully treated with corticosteroids and/or thrombopoietin receptor agonists (TPO-RAs). These results suggest that increased RP% and detection of glycoprotein-specific platelet autoantibodies are useful for the diagnosis of ITP after HSCT.


Assuntos
Autoanticorpos/sangue , Plaquetas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Contagem de Plaquetas , Glicoproteínas da Membrana de Plaquetas/imunologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/etiologia , Transplante Homólogo/efeitos adversos , Adolescente , Corticosteroides/uso terapêutico , Adulto , Biomarcadores/sangue , Plaquetas/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/tratamento farmacológico
9.
J Thromb Haemost ; 20(4): 961-974, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35032087

RESUMO

BACKGROUND: A rapid immune response is critical to ensure effective protection against COVID-19. Platelets are first-line sentinels of the vascular system able to rapidly alert and stimulate the immune system. However, their role in the immune response to vaccines is not known. OBJECTIVE: To identify features of the platelet-immune crosstalk that would provide an early readout of vaccine efficacy in adults who received the mRNA-based COVID-19 vaccine (BNT162b2). METHODS: We prospectively enrolled 11 young healthy volunteers (54% females, median age: 28 years) who received two doses of BNT162b2, 21 days apart, and we studied their platelet and immune response before and after each dose of the vaccine (3 and 10 ± 2 days post-injection), in relation to the kinetics of the humoral response. RESULTS: Participants achieving an effective level of neutralizing antibodies before the second dose of the vaccine (fast responders) had a higher leukocyte count, mounted a rapid cytokine response that incremented further after the second dose, and an elevated platelet turnover that ensured platelet count stability. Their circulating platelets were not more reactive but expressed lower surface levels of the immunoreceptor tyrosine-based inhibitory motif (ITIM)-coupled receptor CD31 (PECAM-1) compared to slow responders, and formed specific platelet-leukocyte aggregates, with B cells, just 3 days after the first dose, and with non-classical monocytes and eosinophils. CONCLUSION: We identified features of the platelet-immune crosstalk that are associated with the development of a rapid humoral response to an mRNA-based vaccine (BNT162b2) and that could be exploited as early biomarkers of vaccine efficacy.


Assuntos
Vacina BNT162 , Plaquetas/imunologia , COVID-19 , Imunidade Humoral , Eficácia de Vacinas , Adulto , Anticorpos Antivirais/sangue , Vacina BNT162/imunologia , COVID-19/prevenção & controle , Feminino , Humanos , Masculino , SARS-CoV-2
10.
JCI Insight ; 7(2)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35076023

RESUMO

Platelet-neutrophil aggregates (PNAs) facilitate neutrophil activation and migration and could underpin the recruitment of neutrophils to the pancreas during type 1 diabetes (T1D) pathogenesis. PNAs, measured by flow cytometry, were significantly elevated in the circulation of autoantibody-positive (Aab+) children and new-onset T1D children, as well as in pre-T1D (at 4 weeks and 10-12 weeks) and T1D-onset NOD mice, compared with relevant controls, and PNAs were characterized by activated P-selectin+ platelets. PNAs were similarly increased in pre-T1D and T1D-onset NOD isolated islets/insulitis, and immunofluorescence staining revealed increased islet-associated neutrophil extracellular trap (NET) products (myeloperoxidase [MPO] and citrullinated histones [CitH3]) in NOD pancreata. In vitro, cell-free histones and NETs induced islet cell damage, which was prevented by the small polyanionic drug methyl cellobiose sulfate (mCBS) that binds to histones and neutralizes their pathological effects. Elevated circulating PNAs could, therefore, act as an innate immune and pathogenic biomarker of T1D autoimmunity. Platelet hyperreactivity within PNAs appears to represent a previously unrecognized hematological abnormality that precedes T1D onset. In summary, PNAs could contribute to the pathogenesis of T1D and potentially function as a pre-T1D diagnostic.


Assuntos
Plaquetas/imunologia , Agregação Celular/imunologia , Diabetes Mellitus Tipo 1 , Armadilhas Extracelulares , Neutrófilos/imunologia , Pâncreas , Animais , Autoanticorpos/sangue , Criança , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Diagnóstico Precoce , Armadilhas Extracelulares/diagnóstico por imagem , Armadilhas Extracelulares/imunologia , Feminino , Imunofluorescência/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Ativação de Neutrófilo/imunologia , Selectina-P/metabolismo , Pâncreas/imunologia , Pâncreas/patologia
12.
Blood ; 139(10): 1564-1574, 2022 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-34587251

RESUMO

Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30 × 109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post-SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Púrpura Trombocitopênica Idiopática , SARS-CoV-2 , Idoso , Idoso de 80 Anos ou mais , Plaquetas/imunologia , Plaquetas/metabolismo , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Púrpura Trombocitopênica Idiopática/epidemiologia , Púrpura Trombocitopênica Idiopática/imunologia , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Esplenectomia , Reino Unido/epidemiologia
13.
Eur J Haematol ; 108(1): 18-27, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34487584

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count and an increased risk of bleeding. In addition to anti-platelet autoantibodies, CD8+ T cells have been implicated as a mechanism of platelet destruction. The current evidence for the existence of platelet-specific CD8+ T cells in ITP is inconclusive. The purpose of this review is to summarize the studies that investigated CD8+ T cells in ITP and to review the methods that have been used to detect autoreactive CD8+ T cells in other autoimmune diseases.


Assuntos
Autoimunidade , Suscetibilidade a Doenças , Púrpura Trombocitopênica Idiopática/etiologia , Linfócitos T/imunologia , Apoptose/genética , Apoptose/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Biomarcadores , Plaquetas/imunologia , Plaquetas/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citotoxicidade Imunológica , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Regulação da Expressão Gênica , Genes MHC Classe I , Humanos , Ativação Linfocitária/imunologia , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/terapia , Linfócitos T/metabolismo
16.
J Am Soc Nephrol ; 33(2): 259-278, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34907031

RESUMO

Kidney disease is a known risk factor for poor outcomes of COVID-19 and many other serious infections. Conversely, infection is the second most common cause of death in patients with kidney disease. However, little is known about the underlying secondary immunodeficiency related to kidney disease (SIDKD). In contrast to cardiovascular disease related to kidney disease, which has triggered countless epidemiologic, clinical, and experimental research activities or interventional trials, investments in tracing, understanding, and therapeutically targeting SIDKD have been sparse. As a call for more awareness of SIDKD as an imminent unmet medical need that requires rigorous research activities at all levels, we review the epidemiology of SIDKD and the numerous aspects of the abnormal immunophenotype of patients with kidney disease. We propose a definition of SIDKD and discuss the pathogenic mechanisms of SIDKD known thus far, including more recent insights into the unexpected immunoregulatory roles of elevated levels of FGF23 and hyperuricemia and shifts in the secretome of the intestinal microbiota in kidney disease. As an ultimate goal, we should aim to develop therapeutics that can reduce mortality due to infections in patients with kidney disease by normalizing host defense to pathogens and immune responses to vaccines.


Assuntos
COVID-19/etiologia , Síndromes de Imunodeficiência/etiologia , Insuficiência Renal Crônica/complicações , Imunidade Adaptativa , Plaquetas/imunologia , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , Microbioma Gastrointestinal/imunologia , Humanos , Imunidade Inata , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/prevenção & controle , Imunofenotipagem , Modelos Imunológicos , Pandemias , Insuficiência Renal Crônica/imunologia , Fatores de Risco , SARS-CoV-2 , Soroconversão
17.
Pediatr Res ; 91(2): 359-367, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34711945

RESUMO

Sepsis, a dysregulated host response to infection, has been difficult to accurately define in children. Despite a higher incidence, especially in neonates, a non-specific clinical presentation alongside a lack of verified biomarkers has prevented a common understanding of this condition. Platelets, traditionally regarded as mediators of haemostasis and thrombosis, are increasingly associated with functions in the immune system with involvement across the spectrum of innate and adaptive immunity. The large number of circulating platelets (approx. 150,000 cells per microlitre) mean they outnumber traditional immune cells and are often the first to encounter a pathogen at a site of injury. There are also well-described physiological differences between platelets in children and adults. The purpose of this review is to place into context the platelet and its role in immunology and examine the evidence where available for its role as an immune cell in childhood sepsis. It will examine how the platelet interacts with both humoral and cellular components of the immune system and finally discuss the role the platelet proteome, releasate and extracellular vesicles may play in childhood sepsis. This review also examines how platelet transfusions may interfere with the complex relationships between immune cells in infection. IMPACT: Platelets are increasingly being recognised as important "first responders" to immune threats. Differences in adult and paediatric platelets may contribute to differing immune response to infections. Adult platelet transfusions may affect infant immune responses to inflammatory/infectious stimuli.


Assuntos
Plaquetas/metabolismo , Mediadores da Inflamação/metabolismo , Sepse/sangue , Plaquetas/imunologia , Proteínas Sanguíneas/metabolismo , Criança , Humanos , Imunidade Celular , Imunidade Humoral , Imunidade Inata , Recém-Nascido , Proteoma , Sepse/imunologia , Transdução de Sinais
18.
Front Immunol ; 13: 1020712, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36591264

RESUMO

Introduction: Platelets have essential functions as first responders in the immune response to pathogens. Activation and aggregation of platelets in bacterial infections can lead to life-threatening conditions such as arterial thromboembolism or sepsis-associated coagulopathy. Methods: In this study, we investigated the role of complement in Escherichia coli (E. coli)-induced platelet aggregation in human whole blood, using Multiplate® aggregometry, flow cytometry, and confocal microscopy. Results and Discussion: We found that compstatin, which inhibits the cleavage of complement component C3 to its components C3a and C3b, reduced the E. coli-induced platelet aggregation by 42%-76% (p = 0.0417). This C3-dependent aggregation was not C3a-mediated as neither inhibition of C3a using a blocking antibody or a C3a receptor antagonist, nor the addition of purified C3a had any effects. In contrast, a C3b-blocking antibody significantly reduced the E. coli-induced platelet aggregation by 67% (p = 0.0133). We could not detect opsonized C3b on platelets, indicating that the effect of C3 was not dependent on C3b-fragment deposition on platelets. Indeed, inhibition of glycoprotein IIb/IIIa (GPIIb/IIIa) and complement receptor 1 (CR1) showed that these receptors were involved in platelet aggregation. Furthermore, aggregation was more pronounced in hirudin whole blood than in hirudin platelet-rich plasma, indicating that E. coli-induced platelet aggregation involved other blood cells. In conclusion, the E. coli-induced platelet aggregation in human whole blood is partly C3b-dependent, and GPIIb/IIIa and CR1 are also involved in this process.


Assuntos
Plaquetas , Complemento C3b , Escherichia coli , Agregação Plaquetária , Humanos , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Complemento C3b/imunologia , Hirudinas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/imunologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/imunologia , Técnicas In Vitro
19.
Front Immunol ; 12: 766272, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34912339

RESUMO

Bacterial infections are a major cause of morbidity and mortality in chronic lymphocytic leukemia (CLL), and infection risk increases in patients treated with the Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib. Btk and related kinases (like Tec) are expressed in non-leukemic hematopoietic cells and can be targeted by ibrutinib. In platelets, ibrutinib therapy is associated with bleeding complications mostly due to off-target effects. But the ability of platelets to respond to bacteria in CLL, and the potential impact of ibrutinib on platelet innate immune functions remain unknown. FcγRIIA is a tyrosine kinase-dependent receptor critical for platelet activation in response to IgG-coated pathogens. Crosslinking of this receptor with monoclonal antibodies causes downstream activation of Btk and Tec in platelets, however, this has not been investigated in response to bacteria. We asked whether ibrutinib impacts on FcγRIIA-mediated activation of platelets derived from CLL patients and healthy donors after exposure to Staphylococcus aureus Newman and Escherichia coli RS218. Platelet aggregation, α-granule secretion and integrin αIIbß3-dependent scavenging of bacteria were detected in CLL platelets but impaired in platelets from ibrutinib-treated patients and in healthy donor-derived platelets exposed to ibrutinib in vitro. While levels of surface FcγRIIA remained unaffected, CLL platelets had reduced expression of integrin αIIbß3 and GPVI compared to controls regardless of therapy. In respect of intracellular signaling, bacteria induced Btk and Tec phosphorylation in both CLL and control platelets that was inhibited by ibrutinib. To address if Btk is essential for platelet activation in response to bacteria, platelets derived from X-linked agammaglobulinemia patients (lacking functional Btk) were exposed to S. aureus Newman and E. coli RS218, and FcγRIIA-dependent aggregation was observed. Our data suggest that ibrutinib impairment of FcγRIIA-mediated platelet activation by bacteria results from a combination of Btk and Tec inhibition, although off-target effects on additional kinases cannot be discarded. This is potentially relevant to control infection-risk in CLL patients and, thus, future studies should carefully evaluate the effects of CLL therapies, including Btk inhibitors with higher specificity for Btk, on platelet-mediated immune functions.


Assuntos
Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Plaquetas/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de IgG/imunologia , Adenina/farmacologia , Adenina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Plaquetas/imunologia , Escherichia coli , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Piperidinas/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Staphylococcus aureus
20.
Front Immunol ; 12: 790051, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956221

RESUMO

Immune checkpoint inhibitors (ICIs), including antibodies targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1), are being extensively used on advanced human malignancies therapy. The treatment with ICIs have acquired durable tumor inhibition and changed the treatment landscape in lung cancer. Immune-related adverse events including pneumonitis and thyroiditis have been well described, but less frequent events, such as ICIs-induced thrombocytopenia, are now emerging and may sometimes be severe or fatal. Since early detection and prompt intervention are crucial to prevent fatal consequences, it is of outmost importance that medical staff is aware of these potential toxicities and learn to recognize and treat them adequately. This review focuses on the epidemiology, clinical presentation, mechanisms, and clinical management of ICIs-induced thrombocytopenia in patients with lung cancer. We also present a patient with advanced lung adenocarcinoma who received the PD-L1 inhibitor atezolizumab and eventually developed severe thrombocytopenia. The case indirectly suggests that cytokine changes might contribute to immune dysregulation in ICIs-induced thrombocytopenia.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Plaquetas/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Idoso , Plaquetas/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/terapia , Fatores de Risco , Resultado do Tratamento
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