RESUMO
Autoimmune hepatitis (AIH) is characterized by persistent liver inflammation induced by aberrant immune responses. Glycyrrhizic acid (GA), a prominent bioactive ingredient of licorice, has shown potential as a safe and effective treatment for AIH. However, the immune regulatory mechanism by which GA exerts its therapeutic effect on AIH remains elusive. In this study, we found that GA intervention significantly alleviated ConA-induced acute liver injury in mice. Cytometry by time-of-flight (CyTOF) analysis revealed that GA increased the abundance of anti-inflammatory F4/80loCD11bhiMHCIIhi MoMF-1 and decreased the abundance of pro-inflammatory F4/80loCD11bhiiNOShi MoMF-3. Multiplex immunofluorescence demonstrated the infiltration of MoMFs in liver tissues. Single-cell RNA sequencing (scRNA-seq) analysis indicated that GA facilitated the immune activation in MoMFs, regulated gene expression of diverse cytokines secreted by MoMFs, and played a role in shaping the immune microenvironment. By integrating the results of CyTOF with scRNA-seq, our study comprehensively elucidates the immune landscape of ConA-induced liver injury following GA intervention, advancing the understanding of GA's mechanism of action. However, it is important to note that some single-cell data in this study remain raw and require further processing and annotation. Our findings suggest that GA alleviates ConA-induced acute liver injury by regulating the function of MoMFs, opening potential avenues for AIH treatment and management, and providing a theoretical basis for the design of novel MoMFs-centered immunotherapies.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Concanavalina A , Ácido Glicirrízico , Macrófagos , Ácido Glicirrízico/farmacologia , Animais , Camundongos , Macrófagos/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hepatite Autoimune/tratamento farmacológico , Camundongos Endogâmicos C57BL , Fígado/efeitos dos fármacos , Citocinas/metabolismo , Masculino , Anti-Inflamatórios/farmacologiaRESUMO
RATIONALE: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by continuous inflammation of the colonic mucosa. Autoimmune hepatitis (AIH) is a chronic liver disease characterized by hypergammaglobulinemia, circulating autoantibodies, interface hepatitis, and favorable response to immunosuppression. An association between IBD and AIH is uncommon, and experts have suggested that in patients with overlapping IBD and AIH, the anti-tumor necrosis factor agents can be used. Therefore, this study reports a rare case of a patient with liver cirrhosis due to AIH and UC refractory to conventional treatment and discusses the risks and benefits of using anti-tumor necrosis factor in both conditions. PATIENT CONCERNS: A 28-year-old female presented with symptoms of diarrhea, abdominal pain, asthenia, and inappetence, accompanied by abdominal collateral circulation, anemia, alteration of liver enzymes, and elevation of C-reactive protein levels. DIAGNOSES: The patient underwent a liver biopsy, which was consistent with liver cirrhosis due to AIH. Colonoscopy showed an inflammatory process throughout the colon, compatible with moderately active UC. INTERVENTIONS: The patient received mesalazine, azathioprine, and corticotherapy, with no control of the inflammatory process. Faced with refractoriness to drug treatment and side effects of corticosteroids with an increased risk of severe infection due to cirrhosis, we opted to use infliximab for the treatment of UC. The patient presented with a clinical response and infliximab therapy was maintained. OUTCOMES: Eight months after starting infliximab therapy, the patient developed pneumonia with complications from disseminated intravascular coagulation and died. LESSONS SUBSECTIONS: AIH is a rare cause of elevated transaminase levels in patients with UC. The best treatment to control the 2 conditions should be evaluated with vigilance for the side effects of medications, mainly infections, especially in patients with cirrhosis.
Assuntos
Colite Ulcerativa , Hepatite Autoimune , Cirrose Hepática , Humanos , Feminino , Adulto , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/complicações , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/complicações , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/complicações , Medição de Risco , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Infliximab/uso terapêutico , Infliximab/efeitos adversosRESUMO
Post-transplantation primary central nervous system lymphoma (PT-PCNSL) is a rare neoplasm that occurs in immunocompromised patients. It can manifest months or years after transplantation, presenting with various neurological symptoms. A 64-year-old woman, who had received a liver transplant due to autoimmune hepatitis, presented with generalized weakness, headache, and confusion. Further investigation revealed multiple ring-enhancing lesions in the right frontal and temporoparietal regions on brain MRI. A brain biopsy confirmed the diagnosis of PT-PCNSL. This case underscores the importance of considering PT-PCNSL in the differential diagnosis of contrast-enhancing brain lesions in post-transplant patients. Timely recognition of PT-PCNSL is crucial for appropriate management and improved outcomes. To the best of our knowledge, this report describes the first instance of isolated CNS lymphoma in a liver transplant recipient, due to autoimmune hepatitis, successfully brought to complete remission with a rituximab-methotrexate regimen.
Assuntos
Hepatite Autoimune , Transplante de Fígado , Linfoma , Humanos , Pessoa de Meia-Idade , Feminino , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/cirurgia , Neoplasias do Sistema Nervoso Central/cirurgia , Imageamento por Ressonância MagnéticaRESUMO
The thiopurine drugs-azathioprine and mercaptopurine-are purine antimetabolites used for the treatment of autoimmune hepatitis. These drugs undergo metabolism through genetically determined pathways, which influences their effectiveness and toxicity. There is scarce information regarding the clinical effects of measuring drug metabolites in these patients. The goal of the study is to test the clinical significance of measuring thiopurine metabolites in patients unsuccessfully treated with thiopurines. Clinical and laboratory data collected for patients who were treated for autoimmune hepatitis between 2015 and 2018, and did not achieve full remission under thiopurine therapy and had thiopurine metabolite levels measured due to lack of response and suspicious side effects were chosen. We compared clinical and laboratory data before and after the therapy change. The study included 25 tests of thiopurine metabolites in 21 patients. Six tests had therapeutic levels. Three tests showed high levels leading to lowering the drug dose. In 11 cases, levels of 6-thioguanine nucleotide were low; the dose was not changed in 3 of these, and the dose was increased in the remaining 8. Shunting was observed in 5 cases, 2 of which were mild and the dose was not changed. In the remaining 3, the dose was decreased, and allopurinol was added. Significant improvements in liver enzymes were observed following dose adjustments. We showed that, in cases of suboptimal response to thiopurine treatment, measuring thiopurine metabolites had an important role in optimizing therapy. In most patients, changing the dose led to a significant improvement with no need to switch to secondline therapies.
Assuntos
Azatioprina , Hepatite Autoimune , Imunossupressores , Mercaptopurina , Humanos , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/metabolismo , Hepatite Autoimune/sangue , Feminino , Masculino , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapêutico , Mercaptopurina/metabolismo , Mercaptopurina/sangue , Pessoa de Meia-Idade , Azatioprina/uso terapêutico , Adulto , Imunossupressores/uso terapêutico , Idoso , Resultado do Tratamento , Nucleotídeos de Guanina/sangue , Estudos Retrospectivos , Monitoramento de Medicamentos/métodos , Tionucleotídeos/sangueRESUMO
Aspergillus species are common hyphal fungi. In addition to allergies and mycotoxicosis, Aspergillus species can cause various infections known as aspergillosis. Aspergillosis of the respiratory tract, central nervous system, skin and soft tissues is well described. However, musculoskeletal infections due to invasive aspergillosis are not well described. Fungal joint infection due to invasive aspergillosis is a rare form of septic arthritis. In this case report, a patient who admitted to our hospital for liver transplantation and developed knee joint arthritis caused by Aspergillus flavus/Aspergillus oryzae during this process was presented. A 28-year-old male patient with autoimmune hepatitis was admitted to hospital with decompensated liver cirrhosis and encephalopathy. The patient, who was awaiting an emergency liver transplant, developed pain, swelling and limitation of movement in his right knee and appropriate consultations and tests were requested. Three joint fluid cultures taken one day apart and nine days later were positive for fungal growth. Macroscopic examination of the mould growth and microscopic examination with lactophenol cotton blue suggested a species belonging to the A.flavus complex and the isolate was identified as A.flavus/A.oryzae by matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-TOF MS) (EXS 2600, Zybio, China). As a result of ITS gene sequencing, the species was determined to be A.oryzae. As cases have been reported where A.flavus and A.oryzae species could not be distinguished by ITS gene sequencing, the pathogen was defined as A.flavus/oryzae. The patient died of liver disease during treatment with amphotericin B. There are few cases of arthritis caused by Aspergillus species in the literature. Aspergillus species found in joint infections are, Aspergillus fumigatus, A.flavus, Aspergillus niger and Aspergillus terreus species complexes, in order of frequency. A.flavus and A.oryzae are closely related. They are difficult to distinguish by conventional methods, MALDI-TOF MS or ITS region sequencing, which is commonly used for genus/species identification in fungi. The number of Aspergillus arthritis cases is low and the identification methods applied to the species reported as causative agents in most studies can identify at the species complex level. In addition, it can be assumed that species not previously reported as causative agents may be encountered as a result of developments in identification methods. In the few publications in the literature where A.flavus complex was reported as the causative agent of joint infections, it seems possible that some of the agents may be A.flavus and some may be A.oryzae, since the agents were identified at the complex level. There are a limited number of cases in the literature where A.oryzae is the causative agent, particularly in the respiratory tract. A PubMed search using the keywords "A.oryzae infections, arthritis, osteomyelitis" did not reveal any literature on joint infections caused by A.oryzae.
Assuntos
Artrite Infecciosa , Aspergilose , Aspergillus flavus , Aspergillus oryzae , Articulação do Joelho , Humanos , Masculino , Adulto , Aspergillus flavus/isolamento & purificação , Aspergilose/diagnóstico , Aspergilose/microbiologia , Aspergilose/tratamento farmacológico , Artrite Infecciosa/microbiologia , Artrite Infecciosa/diagnóstico , Artrite Infecciosa/tratamento farmacológico , Articulação do Joelho/microbiologia , Aspergillus oryzae/isolamento & purificação , Turquia , Hepatite Autoimune/microbiologia , Hepatite Autoimune/tratamento farmacológico , Transplante de Fígado , Antifúngicos/uso terapêuticoRESUMO
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that can lead to cirrhosis and liver failure. AIH can present in all ages, races, and ethnicities, but it predominantly affects women. As a heterogeneous disease, AIH presents variably in different patients, making diagnosis and treatment a challenge. Currently, the standard treatment for AIH comprises immunosuppressants; however, their long-term use is associated with adverse effects. The pathogenesis of AIH is complex, involving T cells, macrophages, and plasma cells that invade the periportal parenchyma and lead to an inflammatory cascade that can result in liver damage. Due to the complexity of AIH pathogenesis, treatment targets several inflammatory pathways. However, unlike other autoimmune diseases in which targeted treatments have been approved, there has been little progress made in advancing the treatment paradigm for AIH. Major obstacles to progress include challenges in conducting clinical trials, particularly patient recruitment and ensuring a diverse range of backgrounds; poorly defined outcomes to assess treatment response and improved quality of life; and a lack of study designs that account for the stage of disease and variations in treatment. A focus on individualized and steroid-free treatment approaches is needed to improve AIH prognosis and minimize steroid-associated adverse effects.
Assuntos
Hepatite Autoimune , Imunossupressores , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/imunologia , Hepatite Autoimune/terapia , Humanos , Imunossupressores/uso terapêuticoRESUMO
Liver dysfunction in systemic lupus erythematosus (SLE) is caused by disease activity or secondary conditions like coexistent autoimmune liver diseases. In Taiwan, despite sporadically reported cases of SLE-autoimmune hepatitis (AIH) overlap disease, larger-scale monocentric investigations for such overlapping patients are not available. Retrospective analyses were performed in a hospitalized SLE cohort with 805 patients for identifying co-existent AIH from 2014 to 2023, focusing on distinct therapeutic modalities and differential diagnosis between SLE-AIH overlap and lupus hepatitis (LH). There were 5 cases (a 0.6% occurrence), all females aged 25-58 years (44 ± 13). Ages for the SLE diagnosis were 19-51 years (30 ± 13), while ages for the AIH diagnosis were 22-57 years (36 ± 14). Contradictory to interface hepatitis in SLE-AIH overlap, liver biopsy only demonstrated non-specific abnormalities in LH. Liver cirrhosis was identified in SLE-AIH overlap but not in LH. After corticosteroids/azathioprine therapy, there were normalized liver function in all LH. In 2 SLE-AIH overlap cases refractory to such therapy, one received B-cell depletion therapy (annual rituximab infusion, 375 mg/m2 weekly × 4) and another accepted living-donor liver transplantation from sibling due to advanced liver cirrhosis, leading to improved hepatic dysfunction in both.
Assuntos
Hepatite Autoimune , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/complicações , Hepatite Autoimune/complicações , Hepatite Autoimune/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Taiwan/epidemiologia , Adulto Jovem , Azatioprina/uso terapêutico , Rituximab/uso terapêutico , Fígado/patologia , Diagnóstico Diferencial , Cirrose Hepática/complicações , Hospitalização , Corticosteroides/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Fígado , BiópsiaRESUMO
Astaxanthin (ASX) is an oxygen-containing non-vitamin A carotenoid pigment. However, the role of ASX in autoimmune hepatitis (AIH) remains unclear. In this study, a mouse model of AIH is established induced by concanavalin A (ConA). Mass cytometry and single-cell RNA sequencing (scRNA-seq) are used to analyze the potential role of ASX in regulating the immune microenvironment of AIH. ASX treatment effectively alleviated liver damage induced by ConA and downregulated pro-inflammatory cytokines production in mice. Mass cytometry and scRNA-seq analyses revealed a significant increase in the number of CD8+ T cells following ASX treatment. Functional markers of CD8+ T cells, such as CD69, MHC II, and PD-1, are significantly downregulated. Additionally, specific CD8+ T cell subclusters (subclusters 4, 13, 24, and 27) are identified, each displaying distinct changes in marker gene expression after ASX treatment. This finding suggests a modulation of CD8+ T cell function by ASX. Finally, the key transcription factors for four subclusters of CD8+ T cells are predicted and constructed a cell-to-cell communication network based on receptor-ligand interactions probability. In conclusion, ASX holds the potential to ameliorate liver damage by regulating the number and function of CD8+ T cells.
Assuntos
Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Hepatite Autoimune , Xantofilas , Animais , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/genética , Hepatite Autoimune/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos , Xantofilas/farmacologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Citometria de Fluxo/métodos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND AND AIMS: Small series suggest that rituximab could be effective as treatment for autoimmune hepatitis (AIH), although data are scarce. We aimed to evaluate the efficacy and safety of rituximab in different cohorts of patients with AIH. METHODS: Multicentre retrospective analysis of the 35 patients with AIH and its variant forms treated with rituximab and included in the ColHai registry between 2015 and 2023. RESULTS: Most patients were female (83%), 10 (29%) had cirrhosis and four (11.4%) variant forms of AIH. Indication for rituximab were as follows: 14(40%) refractory AIH, 19(54%) concomitant autoimmune or haematological disorder, 2(6%) intolerance to prior treatments. In three (9%) subjects with a concomitant disorder, rituximab was the first therapy for AIH. Overall, 31 (89%) patients achieved or maintained complete biochemical response (CBR), including the three in first-line therapy. No difference in CBR was observed according to rituximab indication (refractory AIH 86% vs. concomitant disorders 90%, p = .824) or cirrhosis (80% vs. 92%, p = .319). Rituximab was associated with a significant reduction in corticosteroids (median dose: prior 20 vs. post 5 mg, p < .001) and the discontinuation of ≥1 immunosuppressant in 47% of patients. Flare-free rate at 1st, 2nd and 3rd year was 86%, 73% and 62% respectively. Flares were not associated with the development of liver failure and were successfully managed with repeated doses of rituximab and/or increased corticosteroids. Three (9%) patients experienced infusion-related adverse events (1 anaphylaxis and 2 flu-like symptoms) and five (14%) infections. CONCLUSION: Rituximab is safe and effective in patients with refractory AIH and those treated due to concomitant autoimmune or haematological disorders.
Assuntos
Hepatite Autoimune , Sistema de Registros , Rituximab , Humanos , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Feminino , Hepatite Autoimune/tratamento farmacológico , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Idoso , Resultado do Tratamento , Fatores Imunológicos/uso terapêutico , Fatores Imunológicos/efeitos adversos , Adulto JovemRESUMO
Yinchenhao Decoction (YCHD) is a classic prescription in traditional Chinese medicine (TCM). It appears to play an important role in anti-inflammation and autoimmunity protection. As one of the key active ingredients in YCHD, quercetin is a novel anti-inflammatory metabolite that exerts protective effects in many autoimmune diseases. However, its role in autoimmune hepatitis (AIH)-related hepatic injury has not been studied. The aim of this study was to reveal the hepatocyte protective mechanism of quercetin. In this study, we used Concanavalin A (Con A) to establish an in vitro hepatocyte injury-associated AIH model. Brl3a hepatocyte injury was induced by the supernatant of J774A.1 cells treated with Con A. We found that quercetin mitigated Con A-induced via macrophage-mediated Brl3a hepatocyte injury. Quercetin administration reduced the levels of alanine transaminase (ALT) and aspartate transaminase (AST) in the supernatant of Con A-treated Brl3a cells and attenuated the infiltration of J774A.1 macrophages induced by Con A. Moreover, quercetin effectively inhibited the expression of proinflammatory cytokines including interleukin-1ß (IL-1ß) by Con A. Furthermore, quercetin decreased hepatocyte apoptosis and ferroptosis levels in the macrophage-induced hepatocyte injury model. In conclusion, our study indicates that quercetin alleviates macrophage-induced hepatocyte damage by reducing the inflammatory response, apoptosis and ferroptosis. Our work suggests that quercetin might be a potential therapeutic strategy for AIH.
Assuntos
Anti-Inflamatórios , Apoptose , Ferroptose , Hepatócitos , Macrófagos , Quercetina , Quercetina/farmacologia , Quercetina/uso terapêutico , Animais , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Ferroptose/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Hepatite Autoimune/metabolismo , Hepatite Autoimune/etiologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/imunologia , Concanavalina A , Citocinas/metabolismoRESUMO
BACKGROUND: Autoimmune hepatitis (AIH), primarily mediated by T cells, is characterized by liver inflammation. Despite the advancements in understanding its pathogenesis, effective therapeutic options are limited. Naringin, a flavonoid abundant in citrus fruits, is recognized for its anti-inflammatory properties and ability to protect against various inflammatory diseases, including drug-induced liver injury. However, the exact effects of naringin on AIH and the mechanisms involved remain poorly understood. PURPOSE: We aim to determine the role of naringin in AIH, exploring its targets and actions in this disease. METHODS: Network pharmacology, molecular docking, and molecular dynamics simulations were utilized to predict the HUB targets connecting naringin, T cell-mediated autoimmune disorders, and AIH. Cellular thermal shift assays were used to determine the binding abilities of naringin with the HUB targets. An in vivo experiment confirmed the impact of naringin treatment on AIH development and underlying mechanisms. RESULTS: Naringin demonstrated therapeutic effects on ConA-induced AIH. There were 455 shared targets between naringin, T cell-mediated autoimmune diseases, and AIH. Ten HUB genes (AKT1, ALB, IL-6, IL-1ß, CTNNB1, TNF, TP53, MAPK3, VEGFA, and JUN) were identified through the PPI network. Gene ontology analysis revealed involvement in gene expression regulation, lipopolysaccharide-mediated signaling, and I-kappa kinase/NFκB signaling. Pathway analysis suggested TNF, Th1/Th2 cell differentiation, and Toll-like receptor pathways, with favorable naringin-HUB gene binding. Molecular docking confirmed albumin (ALB), IL-1ß, IL-6, and TNF as primary targets for naringin. Molecular dynamics simulations showed stable binding in ALB-naringin, TNF-naringin, and IL-1ß-naringin complexes. Naringin's hepatoprotective effect on AIH was supported by increased serum ALB and decreased hepatic inflammatory cytokines including IL-1ß, IL-6, and TNF-α. CONCLUSION: Our data underscore the potential of naringin as a preventive or therapeutical agent in T cell-mediated autoimmune diseases including AIH.
Assuntos
Flavanonas , Hepatite Autoimune , Simulação de Acoplamento Molecular , Flavanonas/farmacologia , Flavanonas/química , Hepatite Autoimune/tratamento farmacológico , Animais , Citrus/química , Simulação de Dinâmica Molecular , Fígado/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Masculino , Farmacologia em Rede , Concanavalina A , Camundongos , Humanos , Linfócitos T/efeitos dos fármacosRESUMO
BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) in children presenting in acute liver failure (ALF) can be fatal and often requires liver transplantation (LTx). This individual patient data meta-analysis (IPD) aims to examine management and outcomes of this population, given the lack of large cohort studies on paediatric AIH first presenting as ALF (AIH-ALF). METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement using PubMed and Excerpta Medica dataBASE, and included English studies published between 2000 and 2020. The study included patients under 21 years of age, diagnosed with type 1 or 2 AIH and presenting with ALF. Data extracted included clinical and biochemical characteristics, interventions, and outcomes. RESULTS: Three hundred and thirty eligible patients from 61 studies were identified, with an additional five patients from our institution. The majority were female (66.8%), with a median age of 10. Overall, 59.7% achieved native liver survival (NLS), 35% underwent LTx, and 5% died before LTx. The use of corticosteroids with non-steroid immunomodulators increased the likelihood of NLS by 2.5-fold compared to corticosteroids alone. AIH-1 was associated with 3.3-fold odds for NLS, compared to AIH-2. However, on multivariate analysis, only AIH-1 was identified as an independent predictor for NLS (OR 3.8 [95% CI 1.03-14.2], p = .04). CONCLUSION: While corticosteroids and non-steroid immunomodulators treatment may offer enhanced probability of achieving NLS, treatment regimens for AIH-ALF may need to consider patient-specific factors, especially AIH type. This highlights the potential for NLS in AIH-ALF and suggest a need to identify biomarkers which predict the need for combination immunosuppression to avoid LTx.
Assuntos
Hepatite Autoimune , Falência Hepática Aguda , Transplante de Fígado , Humanos , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/complicações , Hepatite Autoimune/diagnóstico , Falência Hepática Aguda/mortalidade , Falência Hepática Aguda/terapia , Criança , Pré-Escolar , Imunossupressores/uso terapêutico , Masculino , Feminino , Adolescente , Corticosteroides/uso terapêuticoRESUMO
To investigate the protective role of immune response gene 1 (IRG1) and exogenous itaconate in autoimmune hepatitis (AIH) and elucidate the underlying mechanisms. Wild-type and IRG1-/- AIH mouse models were established, and samples of liver tissue and ocular blood were collected from each group of mice to assess the effects of IRG1/itaconate on the expression of pro- and anti-inflammatory cytokines. The levels of liver enzymes and related inflammatory factors were determined using enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR). Liver histomorphology was detected through hematoxylin and eosin staining and then scored for liver injury, and the infiltration levels of tissue-resident memory T (TRM) cells and related molecules in the liver tissue were detected through immunofluorescence staining in vitro. RNA sequencing and gene enrichment analysis were conducted to identify the corresponding molecules and pathways, and lentiviral transfection was used to generate TRM cell lines with IRG1, Jak3, Stat3, and p53 knockdown. Real-time quantitative PCR and western blot were performed to detect the expression levels of relevant mRNAs and proteins in the liver tissue and cells. The percentage of apoptotic cells was determined using flow cytometry. IRG1/itaconate effectively reduced the release of pro-inflammatory cytokines and the pathological damage to liver tissue, thereby maintaining normal liver function. At the same time, IRG1/itaconate inhibited the JAK3/STAT3 signaling pathway, regulated the expression of related downstream proteins, and inhibited the proliferation and promoted the apoptosis of CD69+CD103+CD8+ TRM cells. For the first time, P53 was found to act as a downstream molecule of the JAK3/STAT3 pathway and was regulated by IRG1/itaconate to promote the apoptosis of CD8+ TRM cells. IRG1/itaconate can alleviate concanavalin A-induced autoimmune hepatitis in mice by inhibiting the proliferation and promoting the apoptosis of CD69+CD103+CD8+ TRM cells via the JAK3/STAT3/P53 pathway.
Assuntos
Antígenos de Diferenciação de Linfócitos T , Apoptose , Linfócitos T CD8-Positivos , Proliferação de Células , Hepatite Autoimune , Cadeias alfa de Integrinas , Janus Quinase 3 , Fator de Transcrição STAT3 , Proteína Supressora de Tumor p53 , Animais , Camundongos , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Hepatite Autoimune/genética , Hepatite Autoimune/tratamento farmacológico , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismo , Janus Quinase 3/genética , Janus Quinase 3/metabolismo , Janus Quinase 3/antagonistas & inibidores , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Fígado/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/imunologia , Células T de Memória/imunologia , Células T de Memória/metabolismo , Células T de Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genéticaAssuntos
Bacteriemia , Celulite (Flegmão) , Hepatite Autoimune , Infecções por Pseudomonas , Pseudomonas putida , Humanos , Hepatite Autoimune/complicações , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Bacteriemia/microbiologia , Bacteriemia/diagnóstico , Bacteriemia/complicações , Bacteriemia/imunologia , Bacteriemia/tratamento farmacológico , Celulite (Flegmão)/microbiologia , Celulite (Flegmão)/diagnóstico , Celulite (Flegmão)/tratamento farmacológico , Celulite (Flegmão)/patologia , Infecções por Pseudomonas/diagnóstico , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/imunologia , Pseudomonas putida/isolamento & purificação , Masculino , Antibacterianos/uso terapêutico , Pessoa de Meia-Idade , FemininoRESUMO
INTRODUCTION: Autoimmune disorders often exhibit interconnectedness, although encountering multiple autoimmune conditions in a single patient is uncommon. Multiple autoimmune syndrome is characterized by the presence of at least three distinct autoimmune diseases in an individual. This report outlines the case of a middle-aged woman diagnosed with autoimmune thyroiditis, Sjögren's syndrome, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, and antisynthetase syndrome. Additionally, it includes a literature review encompassing multiple autoimmune syndromes involving five or more autoimmune diseases. OBSERVATION: A 57-year-old woman, with no previous medical history, presented with fever, extensive muscle weakness, progressive exertional dyspnea, inflammatory polyarthralgia, dysphagia, and dry mouth. Clinical examination revealed muscular deficit in the scapular and pelvic girdles, distal muscular deficit, synovitis in the wrists, and features indicative of "mechanic's hand". Laboratory examinations showed cytolysis, cholestasis, elevated muscle enzymes, hypergammaglobulinemia and elevated thyroid stimulating hormone. Immunoassays showed positive results for antinuclear antibodies, anti-histidyl-t-RNA synthetase, anti-Sjögren's-syndrome-related antigen A, anti-ribonucleic-acid-polymerase-III-RP155, anti-fibrillarin, anti-mitochondrial, anti-liver/kidney microsomal type 1, anti-glycoprotein 210, and anti-thyroid peroxidase antibodies. Further investigations led to the diagnosis of a multiple autoimmune syndrome involving autoimmune thyroiditis, Sjögren's syndrome, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, and antisynthetase syndrome. The patient received treatment with intravenous immunoglobulins, corticosteroids, azathioprine, and ursodeoxycholic acid, which resulted in favorable clinical and biological outcomes. CONCLUSION: This patient presented with six concurrent distinct autoimmune disorders, categorizing this case as a type two multiple autoimmune syndrome. The identification of antisynthetase syndrome notably distinguishes this case.
Assuntos
Doenças Autoimunes , Hepatite Autoimune , Cirrose Hepática Biliar , Miosite , Síndrome de Sjogren , Tireoidite Autoimune , Pessoa de Meia-Idade , Feminino , Humanos , Síndrome de Sjogren/complicações , Hepatite Autoimune/complicações , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Cirrose Hepática Biliar/diagnóstico , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Tireoidite Autoimune/complicações , Tireoidite Autoimune/diagnósticoRESUMO
In recent years, immunosuppressants have shown significant success in the treatment of autoimmune diseases. Therefore, there is an urgent need to develop additional immunosuppressants that offer more options for patients. Toosendanin has been shown to have immunosuppressive activity in vitro as well as effects on autoimmune hepatitis (AIH) in vivo. Toosendanin did not induce apoptosis in activated T-cells and affect the survival rate of naive T-cells. Toosendanin did not affect the expression of CD25 or secretion of IL-2 by activated T-cells, and not affect the expression of IL-4 and INF-γ. Toosendanin did not affect the phosphorylation of STAT5, ERK, AKT, P70S6K. However, toosendanin inhibited proliferation of anti-CD3/anti-CD28 mAbs-activated T-cells with IC50 of (10 ± 2.02) nM. Toosendanin arrested the cell cycle in the G0/G1 phase, significantly inhibited IL-6 and IL-17A secretion, promoted IL-10 expression, and inhibited the P38 MAPK pathway. Finally, toosendanin significantly alleviated ConA-induced AIH in mice. In Summary, toosendanin exhibited immunosuppressive activity in vivo and in vitro. Toosendanin inhibits the proliferation of activated T-cells through the P38 MAPK signalling pathway, significantly suppresses the expression of inflammatory factors, enhances the expression of anti-inflammatory factors, and effectively alleviates ConA-induced AIH in mice, suggesting that toosendanin may be a lead compound for the development of novel immunomodulatory agents with improved efficacy and reduced toxicity.
Assuntos
Proliferação de Células , Medicamentos de Ervas Chinesas , Linfócitos T , Triterpenos , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Proliferação de Células/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Camundongos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Medicamentos de Ervas Chinesas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Citocinas/metabolismo , Imunossupressores/farmacologia , Camundongos Endogâmicos BALB C , FemininoRESUMO
BACKGROUND: Autoimmune hepatitis (AIH) is a prevalent liver disease that can potentially lead to hepatic fibrosis and cirrhosis. The prolonged administration of immunosuppressive medications carries significant risks for patients. Purple sweet potato polysaccharide (PSPP), a macromolecule stored in root tubers, exhibits anti-inflammatory, antioxidant, immune-enhancing, and intestinal flora-regulating properties. Nevertheless, investigation into the role and potential mechanisms of PSPP in AIH remains notably scarce. PURPOSE: Our aim was to explore the possible protective impacts of PSPP against concanavalin A (Con A)-induced liver injury in mice. METHODS: Polysaccharide was isolated from purple sweet potato tubers using water extraction and alcohol precipitation, followed by purification through DEAE-52 cellulose column chromatography and Sephadex G-100 column chromatography. A highly purified component was obtained, and its monosaccharide composition was characterized by high performance liquid chromatography (HPLC). Mouse and cellular models induced by Con A were set up to investigate the impacts of PSPP on hepatic histopathology, apoptosis, as well as inflammation- and oxidative stress-related proteins in response to PSPP treatment. RESULTS: The administration of PSPP significantly reduced hepatic pathological damage, suppressed elevation of ALT and AST levels, and attenuated hepatic apoptosis in Con A-exposed mice. PSPP was found to mitigate Con A-induced inflammation by suppressing the TLR4-P2X7R/NLRP3 signaling pathway in mice. Furthermore, PSPP alleviated Con A-induced oxidative stress by activating the PI3K/AKT/mTOR signaling pathway in mice. Additionally, PSPP demonstrated the ability to reduce inflammation and oxidative stress in RAW264.7 cells induced by Con A in vitro. CONCLUSION: PSPP has the potential to ameliorate hepatic inflammation via the TLR4-P2X7R/NLRP3 pathway and inhibit hepatic oxidative stress through the PI3K/AKT/mTOR pathway during the progression of Con A-induced hepatic injury. The results of this study have unveiled the potential hepatoprotective properties of purple sweet potato and its medicinal value for humans. Moreover, this study serves as a valuable reference, highlighting the potential of PSPP-1 as a drug candidate for the treatment of immune liver injury.