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1.
Front Immunol ; 12: 674803, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34594321

RESUMO

Acute pancreatitis (AP) is a leading cause of death and is commonly accompanied by systemic manifestations that are generally associated with a poor prognosis. Many cytokines contribute to pancreatic tissue damage and cause systemic injury. Interleukin-17 (IL-17) is a cytokine that may play a vital role in AP. Specifically, IL-17 has important effects on the immune response and causes interactions between different inflammatory mediators in the AP-related microenvironment. In this literature review, we will discuss the existing academic understanding of IL-17 and the impacts of IL-17 in different cells (especially in acinar cells and immune system cells) in AP pathogenesis. The clinical significance and potential mechanisms of IL-17 on AP deterioration are emphasized. The evidence suggests that inhibiting the IL-17 cytokine family could alleviate the pathogenic process of AP, and we highlight therapeutic strategies that directly or indirectly target IL-17 cytokines in acute pancreatitis.


Assuntos
Imunidade , Interleucina-17/sangue , Pancreatite/epidemiologia , Pancreatite/imunologia , Animais , Modelos Animais de Doenças , Microbioma Gastrointestinal/imunologia , Humanos , Interleucina-17/antagonistas & inibidores , Camundongos , Terapia de Alvo Molecular/métodos , Pancreatite/tratamento farmacológico , Fatores de Risco , Células Th17/imunologia , Resultado do Tratamento
2.
Science ; 373(6561): eabj0486, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34529467
3.
Life Sci ; 280: 119704, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34111461

RESUMO

AIMS: The present study aimed to evaluate the protective action of thymol towards l-arginine-induced acute pancreatitis (AP) by studying the function of rat peritoneal immune cells. MAIN METHODS: Rat peritoneal exudate cells (PECs), obtained 24 h after the injection of l-arginine (350 mg/100 g of b.w.), were evaluated for mitochondrial activity (MTT assay), adherence capacity (methylene-blue assay), and phagocyte enzyme activity (myeloperoxidase, MPO, assay). The activity of α-amylase and free MPO, as well as the concentration of reactive oxygen species (ROS, i.e. O2-), were determined in the peritoneal exudate fluid. Also, serum α-amylase activity determination and pancreatic tissue pathohistological analysis were performed. KEY FINDING: The administered thymol (50 and 100 mg/kg, per os) caused a significant decrease in the PEC mitochondrial activity and adherence capacity when compared with these functions of PECs isolated from rats with AP. A decrease in cellular MPO activity, as well as in the levels of ROS, α-amylase, and free MPO in peritoneal exudates was found in animals treated with thymol compared to the control animals with AP. Additionally, thymol administration prevented an increase in serum α-amylase activity, accompanied by the decrease in pancreatic tissue damage that follows l-arginine application. SIGNIFICANCE: The present results showed that thymol exerts significant immunomodulatory properties and a potential to silence PEC functions in inflammatory conditions such as the AP induced by l-arginine.


Assuntos
Arginina/efeitos adversos , Imunidade Celular/efeitos dos fármacos , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Timol/uso terapêutico , Animais , Células Cultivadas , Granulócitos/efeitos dos fármacos , Granulócitos/imunologia , Granulócitos/patologia , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/imunologia , Pancreatite/patologia , Cavidade Peritoneal/patologia , Ratos , Ratos Wistar
4.
Scand J Immunol ; 94(1): e13049, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33934376

RESUMO

To investigate whether serum-soluble PD-L1 (sPD-L1) is a potential biomarker for identifying sepsis. This study enrolled 64 septic patients, 29 patients with acute appendicitis, 33 patients with acute pancreatitis and 30 healthy volunteers. Sepsis was defined according to the Sepsis 3.0 criteria.[1] The associated clinical parameters were recorded, blood samples were collected on the first day of diagnosis, and serum sPD-L1 levels were measured using enzyme-linked immunosorbent assays. Compared with the control group, a significant increase in sPD-L1 levels was observed in patients with sepsis (n = 64). Increased sPD-L1 expression correlated strongly with increased clinical inflammatory values (CRP, PCT and WBC) and decreased immunological functional parameters (CD3+ , CD4+ and CD8+ cell counts). The area under the ROC curve (AUC) for sPD-L1 in combination with the sequential organ failure assessment (SOFA) score was superior to the AUC for either sPD-L1 or SOFA score in regard to the diagnosis of sepsis. sPD-L1 may represent a valuable biomarker for the diagnosis of sepsis.


Assuntos
Antígeno B7-H1/sangue , Biomarcadores/sangue , Sepse/sangue , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Antígeno B7-H1/imunologia , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Pancreatite/sangue , Pancreatite/imunologia , Prognóstico , Curva ROC , Sepse/imunologia , Adulto Jovem
5.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808340

RESUMO

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by ductal obstructions, tissue fibrosis, atrophy and exocrine and endocrine pancreatic insufficiency. However, our understanding is very limited concerning the disease's progression from a single acute inflammation, via recurrent acute pancreatitis (AP) and early CP, to the late stage CP. Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor enzyme activated mostly by oxidative DNA damage. As a co-activator of inflammatory transcription factors, PARP1 is a central mediator of the inflammatory response and it has also been implicated in acute pancreatitis. Here, we set out to investigate whether PARP1 contributed to the pathogenesis of CP. We found that the clinically used PARP inhibitor olaparib (OLA) had protective effects in a murine model of CP induced by multiple cerulein injections. OLA reduced pancreas atrophy and expression of the inflammatory mediators TNFα and interleukin-6 (IL-6), both in the pancreas and in the lungs. Moreover, there was significantly less fibrosis (Masson's trichrome staining) in the pancreatic sections of OLA-treated mice compared to the cerulein-only group. mRNA expression of the fibrosis markers TGFß, smooth muscle actin (SMA), and collagen-1 were markedly reduced by OLA. CP was also induced in PARP1 knockout (KO) mice and their wild-type (WT) counterparts. Inflammation and fibrosis markers showed lower expression in the KO compared to the WT mice. Moreover, reduced granulocyte infiltration (tissue myeloperoxidase activity) and a lower elevation of serum amylase and lipase activity could also be detected in the KO mice. Furthermore, primary acinar cells isolated from KO mice were also protected from cerulein-induced toxicity compared to WT cells. In summary, our data suggest that PARP inhibitors may be promising candidates for repurposing to treat not only acute but chronic pancreatitis as well.


Assuntos
Pancreatite/fisiopatologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Células Acinares/metabolismo , Doença Aguda , Animais , Ceruletídeo/farmacologia , Modelos Animais de Doenças , Fibrose , Inflamação/patologia , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pâncreas/metabolismo , Pancreatite/imunologia , Pancreatite Crônica/patologia , Poli(ADP-Ribose) Polimerase-1/fisiologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
Medicine (Baltimore) ; 100(16): e25351, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33879665

RESUMO

RATIONALE: Primary varicella-zoster virus (VZV) infection may be associated with hemophagocytic lymphohistiocytosis (HLH), as well as with acute pancreatitis. However, there is few data concerning the evolution and the optimal treatment of these rare associations. PATIENT CONCERNS: A 57-year-old immunocompromised woman, who was treated for chronic lymphocytic leukemia 3 years prior to admission, was hospitalized with abdominal pain revealing severe acute pancreatitis. The day after admission, a pruritic rash appeared on her face, trunk, and limbs, sparing the palmoplantar regions. At the same time, fever, thrombocytopenia (27 × 109/L), major hyperferritinemia (11,063 µg/mL), hypertriglyceridemia (2.56 mmol/L) and elevated lactate dehydrogenase levels (1441 IU/L) suggested HLH. DIAGNOSIS: The diagnosis of chickenpox (varicella) was established. Primary VZV infection was then confirmed: cutaneous and plasma VZV polymerase chain reactions were positives, VZV serology was negative for IgG. INTERVENTIONS: Treatment with aciclovir was started intravenously after the onset of the rash, for a total of 10 days. A 48-h surveillance in intensive care was carried out. OUTCOMES: Acute pancreatitis and biological abnormalities evolved favorably under aciclovir. Platelet count was normalized 6 days after admission to hospital. LESSONS: A favorable outcome of primary VZV infection associated with severe acute pancreatitis and probable HLH in an immunocompromised patient is possible with aciclovir alone.


Assuntos
Herpesvirus Humano 3/imunologia , Hospedeiro Imunocomprometido/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Pancreatite/imunologia , Infecção pelo Vírus da Varicela-Zoster/imunologia , Doença Aguda , Feminino , Humanos , Linfo-Histiocitose Hemofagocítica/virologia , Pessoa de Meia-Idade , Pancreatite/virologia , Infecção pelo Vírus da Varicela-Zoster/virologia
7.
J Interferon Cytokine Res ; 41(2): 72-80, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33621134

RESUMO

Severe acute pancreatitis (SAP), which is characterized by acute onset and high mortality, is complicated with systemic inflammatory response syndrome. This study investigated the molecular mechanism underlying SAP-induced intestinal mucosal barrier injury. SAP was established in rats by retrograde injection of sodium taurocholate (STC) into biliopancreatic duct. Transfection of miR-99a mimic was conducted 24 h before the SAP establishment. Histological properties of pancreatic and intestinal tissues were observed by hematoxylin-eosin staining. The serum levels of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, procalcitonin (PCT), endotoxin (ET), and diamine oxidase (DAO) were measured by enzyme-linked immunosorbent assay. The expressions of miR-99a, NADPH oxidase (NOX)4, zonula occludens (ZO)-1, occludin, and claudin-1 in pancreatic and the intestinal tissue were determined by quantitative reverse transcription polymerase chain reaction or Western blot. STC injection damaged pancreatic and intestinal tissues of the rats. During the model construction, the serum levels of IL-1ß, TNF-α, PCT, ET, and DAO were increased, whereas miR-99a expression in pancreatic and intestinal tissues of the rats was decreased. miR-99a mimic alleviated SAP-induced histological abnormality of pancreatic and intestinal tissues; moreover, it reversed the serum levels of IL-1ß, TNF-α, PCT, ET, and DAO increased by SAP, decreased SAP-increased NOX4 expression and increased the expressions of ZO-1, occludin, and claudin-1 previously decreased by SAP in pancreatic and the intestinal tissues. Thus, overexpressed miR-99a could alleviate intestinal mucosal barrier injury in rats with SAP.


Assuntos
Mucosa Intestinal/imunologia , MicroRNAs/genética , Pancreatite/genética , Animais , Mucosa Intestinal/patologia , Masculino , MicroRNAs/imunologia , Pancreatite/imunologia , Pancreatite/patologia , Ratos , Ratos Sprague-Dawley
8.
Int Immunopharmacol ; 94: 107486, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33639566

RESUMO

BACKGROUND: Docosahexaenoic acid-derived protectin D1 (PD1) was identified critical in the resolution of inflammation in vivo, where it modulates the innate immune response and stimulates resolution. Acute pancreatitis (AP) is characterized by local pancreatic inflammation with mild forms whereas systemic inflammation with severe forms. Herein we investigate the impact of PD1 in murine models of pancreatitis. METHODS: Three independent AP models, which induced in male mice via intraperitoneal injection of caerulein, L-arginine or pancreatic duct ligation, were used to confirm the protective effect of PD1. Infiltrationsof neutrophils and macrophages in pancreas were detected by flow cytometry and immunohistochemistry. In vitro and in vivo neutrophil extracellular traps formation was detected by immunofluorescence staining. Expression of peptidylarginine deiminase 4 (PAD4) in activated neutrophils was evaluated by western blotting. RESULTS: Systemic treatment with PD1 reduced serum activities of amylase and lipase, blunted the concentrations of tumor necrosis factor-α and interleukin-6 in serum and protected against pancreas histologic damage in three AP models. PD1 also prolonged the survival in the pancreatic duct ligation model. Moreover, pancreatic infiltrationofneutrophils and neutrophil CitH3 expression were reduced after PD1 administration. In vitro studies revealed PD1 decreased supernatant cell-free DNA and CitH3 levels and downregulated PAD4 expression in mouse bone-marrow derived neutrophils. However, in the caerulein mice pretreated with GSK484 hydrochloride, an inhibitor of PAD4, PD1 treatment showed no more protective effect. CONCLUSIONS: PD1 ameliorates AP by decreasing early infiltration of neutrophils into the pancreas and neutrophil extracellular traps formation through PAD4. These results supply the foundation to consider PD1 as a therapy for AP.


Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , Armadilhas Extracelulares/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Animais , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/farmacologia , Armadilhas Extracelulares/imunologia , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos ICR , Neutrófilos/imunologia , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/imunologia , Pancreatite/patologia , Proteína-Arginina Desiminase do Tipo 4/imunologia
9.
Int Immunopharmacol ; 94: 107496, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33639565

RESUMO

OBJECTIVES: Cathepsin B (CTSB), nod-like receptor family pyrin domain-containing 3 (NLRP3), and caspase-1 play an important role in the development of Acute Pancreatitis (AP). Besides, the relationship between the proteins remains poorly understood. In addition, whereas previous studies have found caspase-1 activation in AP, pyroptosis, a caspase-1 induced cell death mode, has never been proposed and proved in AP. METHODS: We induced AP in mice by intraperitoneal injection of cerulein. Mice in the inhibitor group of CTSB were pretreated with injection of CA-074me, while mice in the inhibitor group of caspase-1 were of Ac-YVAD-CHO, 1 h earlier. We evaluated the inflammation of the pancreas and the detected expression of activated CTSB, NLRP3, ASC, caspase-1p20, IL-1ß and IL-18. TUNEL staining was used to detect acinar cell death. RESULTS: The inflammation of the pancreas in the two inhibitor groups was significantly reduced compared with that in the AP group. We observed that CA-074me not only inhibits CTSB, but also suppresses the expression and activity of NLRP3, ASC and caspase-1. We found that CA-074me further inhibits the downstream event of caspase-1, including pro-inflammatory cytokine secretion and pyroptosis. Whereas Ac-YVAD-CHO inhibited caspase-1 and decreased pro-inflammatory cytokine secretion and pyroptosis, it did not down-regulate the expression and activity ofCTSB, NLRP3 and ASC. CONCLUSION: The results indicate that CTSB may aggravate AP by activating the NLRP3 inflammasome and promoting Caspase-1-induced pyroptosis. These provide clues about the pathophysiological mechanisms of AP, shedding light on new ideas and potential targets for the prevention and treatment of AP.


Assuntos
Catepsina B/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pancreatite/imunologia , Animais , Caspase 1/imunologia , Ceruletídeo , Interleucina-1beta/sangue , Masculino , Camundongos Endogâmicos C57BL , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/sangue , Pancreatite/induzido quimicamente , Pancreatite/patologia , Piroptose
10.
Eur J Immunol ; 51(5): 1182-1194, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33521935

RESUMO

Stringent regulation of the inflammatory response is crucial for normal tissue regeneration. Here, we analyzed the role of Toll-like receptor 3 (TLR3) in pancreatic regeneration after acute pancreatitis (AP). AP was induced by caerulein treatment in mice with global TLR3 deficiency (TLR3OFF ) or in mice re-expressing TLR3 exclusively in the myeloid cell lineage (TLR3Mye ). Compared to WT mice, TLR3OFF mice had a markedly increased formation of acinar-to-ductal metaplasia (ADM) that persisted until day 7 after initiation of AP. Pancreatic tissue of WT mice was completely regenerated after 5 days with no detectable ADM structures. The enhancing effect of TLR3-deficiency on ADM formation was closely linked with an increased and prolonged accumulation of macrophages in pancreata of TLR3OFF mice. Importantly, the phenotype of TLR3OFF mice was rescued in TLR3Mye mice, demonstrating the causative role of myeloid cell selective TLR3 signaling. Moreover, in vitro stimulation of macrophages through TLR3 initiated cell death by a caspase-8-associated mechanism. Therefore, these findings provide evidence that TLR3 signaling in myeloid cells is sufficient to limit inflammation and ADM formation and to promote regeneration after AP. Notably, resolution of inflammation after AP was associated with macrophage sensitivity to TLR3-mediated cell death.


Assuntos
Expressão Gênica , Células Mieloides/metabolismo , Pancreatite/genética , Pancreatite/metabolismo , Receptor 3 Toll-Like/genética , Doença Aguda , Animais , Biomarcadores , Proliferação de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Células Mieloides/imunologia , Pancreatite/imunologia , Pancreatite/patologia , Regeneração/genética , Transdução de Sinais , Receptor 3 Toll-Like/metabolismo
11.
J Sci Food Agric ; 101(3): 863-870, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33433910

RESUMO

BACKGROUND: Protecting the intestinal mucosa from being destroyed helps reduce the inflammation caused by acute pancreatitis (AP). In this study, whether okra pectin (OP) could attenuate the inflammation of AP through protecting the intestinal barrier was investigated. RESULTS: OP was obtained from crude okra pectin (COP) through the purification by DEAE cellulose 52 column. Supplementation with OP or COP in advance reduced the severity of AP, as revealed by lower serum amylase and lipase levels, abated pancreatic edema, attenuated myeloperoxidase activity and pancreas histology. OP or COP inhibited the production of pancreatic proinflammatory cytokines, including tumor necrosis factor-α and interleukin-6. In addition, the upregulation of AP-related proteins including ZO-1, occludin, the antibacterial peptide-defensin-1 (DEFB1) and cathelicidin-related antimicrobial peptide (CRAMP), as well as the histological examination of colon injuries, demonstrated that OP or COP provision could effectively maintain intestinal barrier function. Ultimately, dietary OP or COP supplementation could inhibit AP-induced intestinal inflammation. For the above, the effect of OP was better than COP. CONCLUSION: Dietary OP supplementation could be considered as a preventive method that effectively interferes with intestinal damage and attenuates inflammatory responses trigged by AP. © 2020 Society of Chemical Industry.


Assuntos
Abelmoschus/química , Ceruletídeo/efeitos adversos , Mucosa Intestinal/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Pectinas/administração & dosagem , Extratos Vegetais/administração & dosagem , Animais , Citocinas/genética , Citocinas/imunologia , Frutas/química , Humanos , Mucosa Intestinal/imunologia , Masculino , Camundongos , Ocludina/genética , Ocludina/imunologia , Pancreatite/induzido quimicamente , Pancreatite/genética , Pancreatite/imunologia , Pectinas/química , Extratos Vegetais/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/imunologia
12.
Int J Med Sci ; 18(2): 534-545, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33390823

RESUMO

Acute pancreatitis (AP) is a leading cause of gastrointestinal-related hospital admissions with significant morbidity and mortality. Although the underlying pathophysiology of AP is rather complex, which greatly limits the treatment options, more and more studies have revealed that infiltrating immune cells play a critical role in the pathogenesis of AP and determine disease severity. Thus, immunomodulatory therapy targeting immune cells and related inflammatory mediators is expected to be a novel treatment modality for AP which may improve the prognosis of patients. Cells of the innate immune system, including macrophages, neutrophils, dendritic cells, and mast cells, represent the majority of infiltrating cells during AP. In this review, an overview of different populations of innate immune cells and their role during AP will be discussed, with a special focus on neutrophils and macrophages.


Assuntos
Imunidade Inata , Pâncreas/patologia , Pancreatite/imunologia , Animais , Células Dendríticas/imunologia , Modelos Animais de Doenças , Humanos , Imunoterapia/métodos , Macrófagos/imunologia , Mastócitos/imunologia , Neutrófilos/imunologia , Pâncreas/citologia , Pâncreas/imunologia , Pancreatite/patologia , Pancreatite/terapia
14.
J Am Acad Dermatol ; 84(3): 644-653, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32561372

RESUMO

BACKGROUND: Complications involving internal organs are usually present in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, pancreatic complications are rarely reported and studied. OBJECTIVE: To summarize clinical characteristics of SJS/TEN-associated acute pancreatic injuries and to investigate underlying inflammatory mechanisms. METHODS: Clinical records of 124 inpatients with SJS/TEN were reviewed. Serum levels of tumor necrosis factor α, interleukin (IL) 6, IL-18, IL-15, IL-12p70, and soluble CD56 were determined in 18 healthy donors and 17 patients with SJS/TEN, including 3 with acute pancreatic injuries. RESULTS: Acute pancreatic injury was diagnosed in 7.3% of patients (9/124) in the SJS/TEN cohort. Elevation of serum transaminase level and hypoalbuminemia occurred more frequently in patients with acute pancreatic injuries compared with those without pancreatic symptoms (P = .004 and <.001, respectively). Although acute pancreatic injury did not alter mortality rate of SJS/TEN, it was associated with longer hospitalization stays (P = .008). Within the serum cytokines whose levels were elevated in SJS/TEN, only IL-18 was found to be selectively increased in patients with acute pancreatic injuries compared with those without them (P = .03). LIMITATIONS: Cohort was small. CONCLUSION: Acute pancreatic injury is a gastrointestinal complication of SJS/TEN in which hepatotoxicity is more likely to occur. Overexpression of IL-18 might be involved in this unique entity.


Assuntos
Interleucina-18/sangue , Pancreatite/imunologia , Síndrome de Stevens-Johnson/complicações , Adolescente , Adulto , Idoso , Antígeno CD56/sangue , Antígeno CD56/imunologia , Criança , Feminino , Humanos , Interleucina-12/sangue , Interleucina-12/imunologia , Interleucina-15/sangue , Interleucina-15/imunologia , Interleucina-18/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Pancreatite/sangue , Estudos Retrospectivos , Síndrome de Stevens-Johnson/sangue , Síndrome de Stevens-Johnson/imunologia , Síndrome de Stevens-Johnson/mortalidade , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
15.
Gut ; 70(2): 330-341, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32393543

RESUMO

OBJECTIVE: Long-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1ß (IL-1ß) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1ß and chronic pancreatitis might contribute to PDAC progression. DESIGN: We crossed LSL-Kras +/G12D;Pdx1-Cre (KC) mice with transgenic mice overexpressing IL-1ß to generate KC-IL1ß mice, and followed them longitudinally. We used pancreatic 3D in vitro culture to assess acinar-to-ductal metaplasia formation. Immune cells were analysed by flow cytometry and immunohistochemical staining. B lymphocytes were adoptively transferred or depleted in Kras-mutant mice. B-cell infiltration was analysed in human PDAC samples. RESULTS: KC-IL1ß mice developed PDAC with liver metastases. IL-1ß treatment increased Kras+/G12D pancreatic spheroid formation. CXCL13 expression and B lymphocyte infiltration were increased in KC-IL1ß pancreata. Adoptive transfer of B lymphocytes from KC-IL1ß mice promoted tumour formation, while depletion of B cells prevented tumour progression in KC-IL1ß mice. B cells isolated from KC-IL1ß mice had much higher expression of PD-L1, more regulatory B cells, impaired CD8+ T cell activity and promoted tumorigenesis. IL-35 was increased in the KC-IL1ß pancreata, and depletion of IL-35 decreased the number of PD-L1+ B cells. Finally, in human PDAC samples, patients with PDAC with higher B-cell infiltration within tumours showed significantly shorter survival. CONCLUSION: We show here that IL-1ß promotes tumorigenesis in part by inducing an expansion of immune-suppressive B cells. These findings point to the growing significance of B suppressor cells in pancreatic tumorigenesis.


Assuntos
Linfócitos B/imunologia , Carcinoma Ductal Pancreático/etiologia , Tolerância Imunológica/imunologia , Neoplasias Pancreáticas/etiologia , Pancreatite/complicações , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/imunologia , Citometria de Fluxo , Interleucina-1beta/efeitos adversos , Camundongos , Camundongos Transgênicos , Neoplasias Pancreáticas/imunologia , Pancreatite/etiologia , Pancreatite/imunologia
16.
Rheumatology (Oxford) ; 60(7): 3317-3325, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33313857

RESUMO

OBJECTIVES: The 2019 ACR/EULAR classification criteria for IgG4-related disease (IgG4-RD) have exclusion criteria including positive disease-specific autoantibodies, and these have been documented to have a high specificity. This study aimed to further validate these criteria as well as identify characteristics of patients showing false-negative results. METHODS: We retrospectively analysed 162 IgG4-RD patients and 130 mimickers. The sensitivity, specificity and fulfilment rates for each criterion were calculated, and intergroup comparisons were performed to characterize the false-negative cases. RESULTS: Both the IgG4-RD patients and mimickers were aged ≥65 years with male predominance. The final diagnoses of mimickers were mainly malignancy, vasculitis, sarcoidosis and aneurysm. The classification criteria had a sensitivity of 72.8% and specificity of 100%. Of the 44 false-negative cases, one did not fulfil the entry criteria, 20 fulfilled one exclusion criterion and 27 did not achieve sufficient inclusion criteria scores. The false-negative cases had fewer affected organs, lower serum IgG4 levels, and were less likely to have received biopsies than the true-positive cases. Notably, positive disease-specific autoantibodies were the most common exclusion criterion fulfilled in 18 patients, only two of whom were diagnosed with a specific autoimmune disease complicated by IgG4-RD. In addition, compared with the true-positive cases, the 18 had comparable serum IgG4 levels, number of affected organs, and histopathology and immunostaining scores despite higher serum IgG and CRP levels. CONCLUSIONS: The ACR/EULAR classification criteria for IgG4-RD have an excellent diagnostic specificity in daily clinical practice. Positive disease-specific autoantibodies may have limited clinical significance for the diagnosis of IgG4-RD.


Assuntos
Autoanticorpos/imunologia , Doença Relacionada a Imunoglobulina G4/diagnóstico , Idoso , Anticorpos Anti-Proteína Citrulinada/imunologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Anticorpos Antinucleares/imunologia , Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/imunologia , Doenças da Aorta/diagnóstico , Doenças da Aorta/imunologia , Aortite/diagnóstico , Aortite/imunologia , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/imunologia , Dacriocistite/diagnóstico , Dacriocistite/imunologia , Diagnóstico Diferencial , Reações Falso-Negativas , Feminino , Humanos , Doença Relacionada a Imunoglobulina G4/imunologia , Nefropatias/diagnóstico , Nefropatias/imunologia , Linfoma/diagnóstico , Linfoma/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/imunologia , Pancreatopatias/diagnóstico , Pancreatopatias/imunologia , Pancreatite/diagnóstico , Pancreatite/imunologia , Estudos Retrospectivos , Doenças das Glândulas Salivares/diagnóstico , Doenças das Glândulas Salivares/imunologia , Sarcoidose/diagnóstico , Sarcoidose/imunologia , Sialadenite/diagnóstico , Sialadenite/imunologia
17.
Pancreatology ; 20(8): 1637-1647, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33097430

RESUMO

BACKGROUND: Acute pancreatitis is a gastrointestinal disorder of high incidence resulting in life threatening complications in up to 20% of patients. Its severe form is characterized by an extensive and systemic immune response. We investigated the role of the adaptive immune response in two experimental models of pancreatitis. METHODS: In C57BI/6-mice mild pancreatitis was induced by 8-hourly injections of caerulein and severe pancreatitis by additional, partial pancreatic duct ligation. T-cell-activation was determined by flow-cytometry of CD25/CD69, T-cell-differentiation by nuclear staining of the transcription-factors Tbet, Gata3 and Foxp3. In vivo CD4+ T-cells were depleted using anti-CD4 antibody. Disease severity was determined by histology, serum amylase and lipase activities, lung MPO and serum cytokine levels (IL-6, TNFα, IL-10). RESULTS: In both models T-cells were activated. Th1-differentiation (Tbet) was absent during pancreatitis but we detected a pronounced Th2/Treg (Gata3/Foxp3) response which paralleled disease severity in both models. The complete depletion of CD4+ T-cells via anti-CD4 antibody, surprisingly, reduced disease severity significantly, as well as granulocyte infiltration and pro- and anti-inflammatory cytokine levels. Co-incubation of acini and T-cells did not lead to T-cell-activation by acinar cells but to acinar damage by T-cells. During pancreatitis no significant T-cell-infiltration into the pancreas was observed. CONCLUSION: T cells orchestrate the early local as well as the systemic immune responses in pancreatitis and are directly involved in organ damage. The Th2 response appears to increase disease severity, rather than conferring an immunological protection.


Assuntos
Imunidade Adaptativa , Diferenciação Celular , Pancreatite , Linfócitos T Reguladores , Células Th2 , Animais , Citocinas , Modelos Animais de Doenças , Ativação Linfocitária , Camundongos , Pancreatite/imunologia
18.
Int J Mol Sci ; 21(15)2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32751171

RESUMO

The discovery of inflammasomes has enriched our knowledge in the pathogenesis of multiple inflammatory diseases. The NLR pyrin domain-containing protein 3 (NLRP3) has emerged as the most versatile and well-characterized inflammasome, consisting of an intracellular multi-protein complex that acts as a central driver of inflammation. Its activation depends on a tightly regulated two-step process, which includes a wide variety of unrelated stimuli. It is therefore not surprising that the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Inflammasome-mediated inflammation has become increasingly important in acute pancreatitis, an inflammatory disorder of the pancreas that is one of the fatal diseases of the gastrointestinal tract. This review presents an update on the progress of research into the contribution of the NLRP3 inflammasome to acute pancreatic injury, examining the mechanisms of NLRP3 activation by multiple signaling events, the downstream interleukin 1 family of cytokines involved and the current state of the literature on NLRP3 inflammasome-specific inhibitors.


Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pâncreas/imunologia , Pancreatite/genética , Animais , Regulação da Expressão Gênica , Glibureto/uso terapêutico , Humanos , Indometacina/uso terapêutico , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pancreatite/tratamento farmacológico , Pancreatite/imunologia , Pancreatite/patologia , Transdução de Sinais , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Vitanolídeos/uso terapêutico
19.
EBioMedicine ; 58: 102920, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32739869

RESUMO

BACKGROUND: Impaired or hyperactive pancreas regeneration after injury would cause exocrine insufficiency or recurrent / chronic pancreatitis and potentially carcinogenesis. Macrophages are the most abundant immune cells in the regenerative pancreas, however their phenotype and role remain poorly defined. METHOD: Using caerulein-induced acute pancreatitis (AP) model, we examined the dynamic landscape of pancreatic macrophages throughout the acute inflammation to regeneration phases by flow cytometric and RNA-seq analyses. Liposome depletion of macrophages, Il4ra-/- mice as well as inhibitors were used to elucidate the role and regulatory mechanism of macrophages during pancreatic regeneration. FINDINGS: We found that M1 macrophages dominated in the pro-inflammatory phase of AP, while M2-like macrophages dominated during pancreas repair/regeneration. Depletion of macrophages at early or late regenerative stage dramatically blocked the acinar-ductal metaplasia (ADM) or delayed inflammation resolution, respectively. Moreover, alternative activation of macrophages was partially dependent on IL-4RA signaling, and ECM/AKT activation in pancreatic macrophages facilitated inflammation resolution during tissue regeneration. INTERPRETATION: Our findings illustrate a dynamic phenotype and function of macrophages during AP repair/regeneration, helping us better understand the mechanism of pancreatic regeneration and providing clues for novel therapeutic strategy.


Assuntos
Ceruletídeo/efeitos adversos , Perfilação da Expressão Gênica/métodos , Macrófagos/fisiologia , Pancreatite/imunologia , Receptores de Superfície Celular/genética , Animais , Polaridade Celular , Modelos Animais de Doenças , Lipossomos , Regeneração Hepática , Camundongos , Pancreatite/induzido quimicamente , Pancreatite/genética , Fenótipo , Análise de Sequência de RNA , Cicatrização
20.
Cells ; 9(8)2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32796685

RESUMO

Pancreatitis is a condition of pancreatic inflammation driven by injury to the pancreatic parenchyma. The extent of acinar insult, intensity, and type of immune response determines the severity of the disease. Smoking, alcohol and autoimmune pancreatitis are some of the predominant risk factors that increase the risk of pancreatitis by differentially influencing the adaptive immune system. The overall decrease in peripheral lymphocyte (T-, B- and (natural killer T-) NKT-cell) count and increased infiltration into the damaged pancreatic tissue highlight the contribution of adaptive immunity in the disease pathology. Smoking and alcohol modulate the responsiveness and apoptosis of T- and B-cells during pancreatic insult. Acute pancreatitis worsens with smoking and alcohol, leading to the development of systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome, suggesting the critical role of adaptive immunity in fatal outcomes such as multiple organ dysfunction. The presence of CD4+ and CD8+ T-lymphocytes and perforin-expressing cells in the fibrotic tissue in chronic pancreatitis modulate the severity of the disease. Due to their important role in altering the severity of the disease, attempts to target adaptive immune mediators will be critical for the development of novel therapeutic interventions.


Assuntos
Pancreatite/imunologia , Pancreatite/metabolismo , Doença Aguda , Imunidade Adaptativa/imunologia , Imunidade Adaptativa/fisiologia , Animais , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Humanos , Pâncreas/imunologia , Pâncreas/metabolismo
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