Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),causing coronavirus disease 2019(COVID-19),can trigger autoimmunity in genetically predisposed individuals through hyperstimulation of immune response and mo...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),causing coronavirus disease 2019(COVID-19),can trigger autoimmunity in genetically predisposed individuals through hyperstimulation of immune response and molecular mimicry.Here we summarise the current knowledge about autoimmune liver diseases(AILDs)and SARS-CoV-2,focusing on:(1)The risk of SARS-CoV-2 infection and the course of COVID-19 in patients affected by AILDs;(2)the role of SARS-CoV-2 in inducing liver damage and triggering AILDs;and(3)the ability of vaccines against SARS-CoV-2 to induce autoimmune responses in the liver.Data derived from the literature suggest that patients with AILDs do not carry an increased risk of SARS-Cov-2 infection but may develop a more severe course of COVID-19 if on treatment with steroids or thiopurine.Although SARSCoV-2 infection can lead to the development of several autoimmune diseases,few reports correlate it to the appearance of de novo manifestation of immunemediated liver diseases such as autoimmune hepatitis(AIH),primary biliary cholangitis(PBC)or AIH/PBC overlap syndrome.Different case series of an AIHlike syndrome with a good prognosis after SARS-CoV-2 vaccination have been described.Although the causal link between SARS-CoV-2 vaccines and AIH cannot be definitively established,these reports suggest that this association could be more than coincidental.展开更多
BACKGROUND Noninvasive methods have been developed to detect fibrosis in many liver diseases due to the limits of liver biopsy.However,previous studies have focused primarily on chronic viral hepatitis and nonalcoholi...BACKGROUND Noninvasive methods have been developed to detect fibrosis in many liver diseases due to the limits of liver biopsy.However,previous studies have focused primarily on chronic viral hepatitis and nonalcoholic fatty liver disease.The diagnostic value of transient elastography for autoimmune liver diseases(AILDs)is worth studying.AIM To compare the diagnostic accuracy of imaging techniques with serum biomarkers of fibrosis in AILD.METHODS The PubMed,Cochrane Library and EMBASE databases were searched.Studies evaluating the efficacy of noninvasive methods in the diagnosis of AILDs[autoimmune hepatitis(AIH),primary biliary cholangitis(PBC)and primary sclerosing cholangitis(PSC)]were included.The summary area under the receiver operating characteristic curve(AUROC),diagnostic odds ratio,sensitivity and specificity were used to assess the accuracy of these noninvasive methods for staging fibrosis.RESULTS A total of 60 articles were included in this study,and the number of patients with AIH,PBC and PSC was 1594,3126 and 501,respectively.The summary AUROC of transient elastography in the diagnosis of significant fibrosis,advanced fibrosis and cirrhosis in patients with AIH were 0.84,0.88 and 0.90,respectively,while those in patients with PBC were 0.93,0.93 and 0.91,respectively.The AUROC of cirrhosis for patients with PSC was 0.95.However,other noninvasive indices(aspartate aminotransferase to platelet ratio index,aspartate aminotransferase/alanine aminotransferase ratio,fibrosis-4 index)had corresponding AUROCs less than 0.80.CONCLUSION Transient elastography exerts better diagnostic accuracy in AILD patients,especially in PBC patients.The appropriate cutoff values for staging advanced fibrosis and cirrhosis ranged from 9.6 to 10.7 and 14.4 to 16.9 KPa for PBC patients.展开更多
BACKGROUND Hepatic steatosis commonly occurs in some chronic liver diseases and may affect disease progression.AIM To investigate the performance of controlled attenuation parameter(CAP)for the diagnosis of hepatic st...BACKGROUND Hepatic steatosis commonly occurs in some chronic liver diseases and may affect disease progression.AIM To investigate the performance of controlled attenuation parameter(CAP)for the diagnosis of hepatic steatosis in patients with autoimmune liver diseases(AILDs).METHODS Patients who were suspected of having AILDs and underwent liver biopsy were consistently enrolled.Liver stiffness measurement(LSM)and CAP were performed by transient elastography.The area under the receiver operating characteristic(AUROC)curve was used to evaluate the performance of CAP for diagnosing hepatic steatosis compared with biopsy.RESULTS Among 190 patients with biopsy-proven hepatic steatosis,69 were diagnosed with autoimmune hepatitis(AIH),18 with primary biliary cholangitis(PBC),and 27 with AIH-PBC overlap syndrome.The AUROCs of CAP for the diagnosis of steatosis in AILDS were 0.878(0.791-0.965)for S1,0.764(0.676-0.853)for S2,and 0.821(0.716-0.926)for S3.The CAP value was significantly related to hepatic steatosis grade(P<0.001).Among 69 patients with AIH,the median CAP score was 205.63±47.36 dB/m for S0,258.41±42.83 dB/m for S1,293.00±37.18 dB/m for S2,and 313.60±27.89 dB/m for S3.Compared with patients with nonalcoholic fatty liver disease(NAFLD)presenting with autoimmune markers,patients with AIH concomitant with NAFLD were much older and had higher serum IgG levels and LSM values.CONCLUSION CAP can be used as a noninvasive diagnostic method to evaluate hepatic steatosis in patients with AILDs.Determination of LSM combined with CAP may help to identify patients with AIH concomitant with NAFLD from those with NAFLD with autoimmune phenomena.展开更多
More than 90%of cases of hepatocellular carcinoma(HCC)occurs in patients with cirrhosis,of which hepatitis B virus and hepatitis C virus are the leading causes,while the tumor less frequently arises in autoimmune live...More than 90%of cases of hepatocellular carcinoma(HCC)occurs in patients with cirrhosis,of which hepatitis B virus and hepatitis C virus are the leading causes,while the tumor less frequently arises in autoimmune liver diseases.Advances in understanding tumor immunity have led to a major shift in the treatment of HCC,with the emergence of immunotherapy where therapeutic agents are used to target immune cells rather than cancer cells.Regulatory T cells(Tregs)are the most abundant suppressive cells in the tumor microenvironment and their presence has been correlated with tumor progression,invasiveness,as well as metastasis.Tregs are characterized by the expression of the transcription factor Foxp3 and various mechanisms ranging from cell-to-cell contact to secretion of inhibitory molecules have been implicated in their function.Notably,Tregs amply express checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4 and programmed cell-death 1 receptor and therefore represent a direct target of immune checkpoint inhibitor(ICI)immunotherapy.Taking into consideration the critical role of Tregs in maintenance of immune homeostasis as well as avoidance of autoimmunity,it is plausible that targeting of Tregs by ICI immunotherapy results in the development of immune-related adverse events(irAEs).Since the use of ICI becomes common in oncology,with an increasing number of new ICI currently under clinical trials for cancer treatment,the occurrence of irAEs is expected to dramatically rise.Herein,we review the current literature focusing on the role of Tregs in HCC evolution taking into account their opposite etiological function in viral and autoimmune chronic liver disease,and we discuss their involvement in irAEs due to the new immunotherapies.展开更多
AIM To determine the diagnostic accuracy of two-dimensional shear wave elastography(2D-SWE) for the noninvasive assessment of liver fibrosis in patients with autoimmune liver diseases(AILD) using liver biopsy as the r...AIM To determine the diagnostic accuracy of two-dimensional shear wave elastography(2D-SWE) for the noninvasive assessment of liver fibrosis in patients with autoimmune liver diseases(AILD) using liver biopsy as the reference standard.METHODS Patients with AILD who underwent liver biopsy and 2D-SWE were consecutively enrolled. Receiver operating characteristic(ROC) curves were constructed to assess the overall accuracy and to identify optimal cut-off values.RESULTS The characteristics of the diagnostic performance were determined for 114 patients with AILD. The areas under the ROC curves for significant fibrosis, severe fibrosis, and cirrhosis were 0.85, 0.85, and 0.86, respectively, and the optimal cut-off values associated with significant fibrosis(≥ F2), severe fibrosis(≥ F3), and cirrhosis(F4) were 9.7 k Pa, 13.2 k Pa and 16.3 k Pa, respectively. 2D-SWE showed sensitivity values of 81.7% for significant fibrosis, 83.0% for severe fibrosis,and 87.0% for cirrhosis, and the respective specificity values were 81.3%, 74.6%, and 80.2%. The overall concordance rate of the liver stiffness measurements obtained using 2D-SWE vs fibrosis stages was 53.5%.CONCLUSION2D-SWE showed promising diagnostic performance for assessing liver fibrosis stages and exhibited high cut-off values in patients with AILD. Low overall concordance rate was observed in the liver stiffness measurements obtained using 2D-SWE vs fibrosis stages.展开更多
Systemic rheumatic diseases(SRDs)are chronic,inflammatory,autoimmune disorders with the presence of autoantibodies that may affect any organ or system.Liver dysfunction in SRDs can be associated with prescribed drugs,...Systemic rheumatic diseases(SRDs)are chronic,inflammatory,autoimmune disorders with the presence of autoantibodies that may affect any organ or system.Liver dysfunction in SRDs can be associated with prescribed drugs,viral hepatitis,alternative hepatic comorbidities and coexisting autoimmune liver diseases(AILDs),requiring an exclusion of secondary conditions before considering liver involvement.The patterns of overlap diseases depend predominantly on genetic determinants with common susceptible loci widely distributing in both disorders.In AILDs,it is important to identify the overlapping SRDs at an early stage since such a coexistence may influence the disease course and prognosis.Commonly co-occurring SRDs in AILDs are Sjögren syndrome(SS),rheumatoid arthritis(RA)or systemic lupus erythematosus(SLE)in autoimmune hepatitis(AIH),and SS,RA or systemic sclerosis in primary biliary cholangitis.Owing to different disease complications and therapies,it is imperative to differentiate between SLE liver involvement and SLE-AIH overlap disease.Therapeutic options can be personalized to control coexisting conditions of liver autoimmunity and rheumatic manifestations in AILD-SRD overlap diseases.The collaboration between hepatologists and rheumatologists can lead to significant advances in managing such a complex scenario.In this review,we provide a comprehensive overview on coexisting AILDs in different SRDs and the therapeutic approach in managing these overlap diseases.展开更多
Intestinal homeostasis depends on complex interactions between the gut microbiota and host immune system.Emerging evidence indicates that the intestinal microbiota is a key player in autoimmune liver disease(AILD).Aut...Intestinal homeostasis depends on complex interactions between the gut microbiota and host immune system.Emerging evidence indicates that the intestinal microbiota is a key player in autoimmune liver disease(AILD).Autoimmune hepatitis,primary biliary cholangitis,primary sclerosing cholangitis,and IgG4-related sclerosing cholangitis have been linked to gut dysbiosis.Diverse mechanisms contribute to disturbances in intestinal homeostasis in AILD.Bacterial translocation and molecular mimicry can lead to hepatic inflammation and immune activation.Additionally,the gut and liver are continuously exposed to microbial metabolic products,mediating variable effects on liver immune pathologies.Importantly,microbiota-specific or associated immune responses,either hepatic or systemic,are abnormal in AILD.Comprehensive knowledge about host-microbiota interactions,included but not limited to this review,facilitates novel clinical practice from a microbiome-based perspective.However,many challenges and controversies remain in the microbiota field of AILD,and there is an urgent need for future investigations.展开更多
The coronavirus disease 2019(COVID-19)pandemic has caused changes in the global health system,causing significant setbacks in healthcare systems worldwide.This pandemic has also shown resilience,flexibility,and creati...The coronavirus disease 2019(COVID-19)pandemic has caused changes in the global health system,causing significant setbacks in healthcare systems worldwide.This pandemic has also shown resilience,flexibility,and creativity in reacting to the tragedy.The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection targets most of the respiratory tract,resulting in a severe sickness called acute respiratory distress syndrome that may be fatal in some individuals.Although the lung is the primary organ targeted by COVID-19 viruses,the clinical aspect of the disease is varied and ranges from asymptomatic to respiratory failure.However,due to an unorganized immune response and several affected mechanisms,the liver may also experience liver cell injury,ischemic liver dysfunction,and drug-induced liver injury,which can result in respiratory failure because of the immune system’s disordered response and other compromised processes that can end in multisystem organ failure.Patients with liver cirrhosis or those who have impaired immune systems may be more likely than other groups to experience worse results from the SARS-CoV-2 infection.We thus intend to examine the pathogenesis,current therapy,and consequences of liver damage concerning COVID-19.展开更多
The liver is the front line organ of the immune system.The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens...The liver is the front line organ of the immune system.The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens.This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens,such as food antigens or pathogens.As an immune active organ,the liver functions as a gatekeeping barrier from the outside world,and it can create a rapid and strong immune response,under unfavorable conditions.However,the liver's assumed immune status is anti-inflammatory or immuno-tolerant.Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance.The anatomical structure of the liver can facilitate the preparation of lymphocytes,modulate the immune response against hepatotropic pathogens,and contribute to some of its unique immunological properties,particularly its capacity to induce antigen-specific tolerance.Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane,circulating lymphocytes can closely contact with antigens,displayed by endothelial cells,Kupffer cells,and dendritic cells while passing through the sinusoids.Loss of immune tolerance,leading to an autoaggressive immune response in the liver,if not controlled,can lead to the induction of autoimmune or autoinflammatory diseases.This review mentions the unique features of liver immunity,and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.展开更多
AIM To investigate the levels, ratios, and clinical significance of T helper 17(Th17) cells and regulatory T(Treg) cells in the peripheral blood of patients with autoimmune liver disease(AILD). METHODS F o r t y-t w o...AIM To investigate the levels, ratios, and clinical significance of T helper 17(Th17) cells and regulatory T(Treg) cells in the peripheral blood of patients with autoimmune liver disease(AILD). METHODS F o r t y-t w o A I L D p a t i e n t s w e r e i n c l u d e d i n t h e experimental group(group E), and 11 healthy subjects were recruited as the control group(group C). Flow cytometry was performed to determine the percentages of Th17 and Treg cells in peripheral blood lymphocytes. Furthermore, a range of biochemical indices was measured simultaneously in the blood of group E patients. RESULTS The percentage of Th17 cells and the Th17/Treg ratio were higher in group E than in group C(P < 0.01), whereas the percentage of Tregs was lower in the group E patients(P < 0.05). Patients in group E who were admitted with AILD in the active stage showed significantly higher Th17 percentages and Th17/Treg ratios than those measured in patients with AILD in remission(P < 0.05). In addition, among patients with AILD in the active stage, individuals that remained unhealed after hospitalization showed significantly higher baseline values of the Th17 percentage and the Th17/Treg ratio than those detected in patients who improved after treatment(P < 0.05). The results suggested that imbalance in the Th17/Treg ratio plays an important role in the pathogenesis and development of AILD.CONCLUSION A high Th17/Treg ratio appears to predict poor shortterm prognosis in patients with AILD in the active stage.展开更多
γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity.Based on the composition of T cell receptor and the cytokines produced,γδT cells can be divided into diverse subsets that may be ...γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity.Based on the composition of T cell receptor and the cytokines produced,γδT cells can be divided into diverse subsets that may be present at different locations,including the liver,epithelial layer of the gut,the dermis and so on.Many of these cells perform specific functions in liver diseases,such as viral hepatitis,autoimmune liver diseases,non-alcoholic fatty liver disease,liver cirrhosis and liver cancers.In this review,we discuss the distribution,subsets,functions ofγδT cells and the relationship between the microbiota andγδT cells in common hepatic diseases.AsγδT cells have been used to cure hematological and solid tumors,we are interested inγδT cell-based immunotherapies to treat liver diseases.展开更多
BACKGROUND Autoimmune liver disease(AILD)has been considered a relatively uncommon disease in China,epidemiological data for AILD in patients with cirrhosis and acute decompensation(AD)is sparse.AIM To investigate the...BACKGROUND Autoimmune liver disease(AILD)has been considered a relatively uncommon disease in China,epidemiological data for AILD in patients with cirrhosis and acute decompensation(AD)is sparse.AIM To investigate the prevalence,outcome and risk factors for AILD in cirrhotic patients complicated with AD in China.METHODS We collected data from patients with cirrhosis and AD from two prospective,multicenter cohorts in hepatitis B virus endemic areas.Patients were regularly followed up at the end of 28-d,90-d and 365-d,or until death or liver transplantation(LT).The primary outcome in this study was 90-d LTfree mortality.Acute-on-chronic liver failure(ACLF)was assessed on admission and during 28-d hospitalization,according to the diagnostic criteria of the European Association for the Study of the Liver(EASL).Risk factors for death were analyzed with logistic regression model.RESULTS In patients with cirrhosis and AD,the overall prevalence of AILD was 9.3%(242/2597).Prevalence of ACLF was significantly lower in AILD cases(14%)than those with all etiology groups with cirrhosis and AD(22.8%)(P<0.001).Among 242 enrolled AILD patients,the prevalence rates of primary biliary cirrhosis(PBC),autoimmune hepatitis(AIH)and PBC-AIH overlap syndrome(PBC/AIH)were 50.8%,28.5%and 12.0%,respectively.In ACLF patients,the proportions of PBC,AIH and PBC/AIH were 41.2%,29.4% and 20.6%.28-d and 90-d mortality were 43.8% and 80.0% in AILD-related ACLF.The etiology of AILD had no significant impact on 28-d,90-d or 365-d LTfree mortality in patients with cirrhosis and AD in both univariate and multivariate analysis.Total bilirubin(TB),hepatic encephalopathy(HE)and blood urea nitrogen(BUN)were independent risk factors for 90-d LT-free mortality in multivariate analysis.The development of ACLF during hospitalization only independently correlated to TB and international normalized ratio.CONCLUSION AILD was not rare in hospitalized patients with cirrhosis and AD in China,among which PBC was the most common etiology.90-d LT-free mortality were independently associated with TB,HE and BUN.展开更多
BACKGROUND Previous reports showed some beneficial effect of oral vancomycin treatment(OVT)in children with primary sclerosing cholangitis;conversely,the experience in patients with other autoimmune liver diseases(AIL...BACKGROUND Previous reports showed some beneficial effect of oral vancomycin treatment(OVT)in children with primary sclerosing cholangitis;conversely,the experience in patients with other autoimmune liver diseases(AILD),including autoimmune hepatitis(AIH)and autoimmune sclerosing cholangitis(ASC),is scant.AIM To assess the response to immunosuppressive treatment(IS)and to OVT in children diagnosed with AILD.METHODS Retrospective study of children diagnosed with AIH(normal biliary tree at cholangiography)and ASC(abnormal biliary tree at cholangiography)in the last 10 years.All underwent standard immunosuppressive therapy(IS),but nonresponders received also OVT.Biochemical remission[normal aspartate aminotransferase(AST)]and immunological remission(normal IgG and negative autoantibodies)rates and Sclerosing Cholangitis Outcomes in Pediatrics(SCOPE)index were assessed and compared during the follow up.RESULTS 75 children were included[69%female,median age 10.5 years(5.6-13.4 years),AIH=54,ASC=21].Sixty-three patients(84%,AIH=52,ASC=11)were treated with standard IS and 61 achieved biochemical remission,whereas 12 not responding to IS[16%,F=75%,median age 13.5 years,(12.2-15.7),10 with ASC]required OVT and 8 achieved biochemical remission.Overall OVT increased the biochemical remission rate of the whole group of AILD patients from 81%(61/75)to 92%(69/75).Median values of AST,alanine aminotransferase(ALT)and gamma-glutamyl transferase(GGT)decreased significantly after OVT start(P<0.05).Complete normalization of livers enzymes(AST,ALT and GGT)was observed in 6/12 patients(50%).Decrease in SCOPE index score was reported in 5/12 patients(42%).At last follow up(median of 4.4 years,range 0.6-13.8 years)all 75 patients are alive,6(8%,1 with ASC)successfully discontinued medications,1(with ASC)required liver transplantation.CONCLUSION Children with AIH and ASC respond well to IS treatment.OVT may represent a valuable treatment option to achieve biochemical remission in patients not responding to standard IS.These promising preliminary results suggest that a prospective study is indicated to define the efficacy of OVT in AILD.展开更多
Regulatory T cells(Treg cells)are crucial for maintaining immune tolerance.Compromising the regulatory function of Treg cells can lead to autoimmune liver disease.However,how Treg cell function is regulated has not be...Regulatory T cells(Treg cells)are crucial for maintaining immune tolerance.Compromising the regulatory function of Treg cells can lead to autoimmune liver disease.However,how Treg cell function is regulated has not been fully clarified.Here,we report that mice with AMP-activated protein kinase alpha 1(AMPKα1)globally knocked out spontaneously develop immune-mediated liver injury,with massive lymphocyte infiltration in the liver,elevated serum alanine aminotransferase levels,and greater production of autoantibodies.Both transplantation of wild-type bone marrow and adoptive transfer of wild-type Treg cells can prevent liver injury in AMPKα1-KO mice.In addition,Treg cell-specific AMPKα1-KO mice display histological features similar to those associated with autoimmune liver disease,greater production of autoantibodies,and hyperactivation of CD4^(+)T cells.AMPKα1 deficiency significantly impairs Treg cell suppressive function but does not affect Treg cell differentiation or proliferation.Furthermore,AMPK is activated upon T cell receptor(TCR)stimulation,which triggers Foxp3 phosphorylation,suppressing Foxp3 ubiquitination and proteasomal degradation.Importantly,the frequency of Treg cells and the phosphorylation levels of AMPK at T172 in circulating blood are significantly lower in patients with autoimmune liver diseases.Conclusion:Our data suggest that AMPK maintains the immunosuppressive function of Treg cells and confers protection against autoimmune liver disease.展开更多
The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology.The liver is a central immunological organ that is particularly enriched in innate immune c...The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology.The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota.The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens.Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases.Of immense importance is the step from high-throughput sequencing(correlation)to mechanistic studies(causality)and therapeutic intervention.Here,we review the gut microbiota,liver immunology,and the interaction between the gut and liver.In addition,the impairment in the gut-liver axis found in various liver diseases is reviewed here,with an emphasis on alcohol-associated liver disease(ALD),nonalcoholic fatty liver disease(NAFLD),and autoimmune liver disease(AILD).On the basis of growing evidence from these preclinical studies,we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.展开更多
The liver is an important immunological organ that controls systemic tolerance.The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance.Orches...The liver is an important immunological organ that controls systemic tolerance.The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance.Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment,which Is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes.In response to pathogens or autoantigens,tolerance is disrupted by unknown mechanisms.Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties.The presentation of microbial and endogenous lipid-,metabolite-and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance.Perturbation of this balance results in autoimmune liver diseases,such as autoimmune hepatitis,primary biliary cholangitis,and primary sclerosing cholangitis.Although the exact etiologies of these autoimmune liver diseases are unknown,it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids,as well as alterations in bile acid composition,may result in changes in effector cell activation and polarization and may reduce or impair protective antiinflammatory regulatory T and B cell responses.Additionally,the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different(non)immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance.Here,we summarize emerging aspects of antigen presentation,autoantibody production,and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.展开更多
Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology.However,inheritance drives the ability to appropriately adapt to environmental stressors,and disease is the culmination of a m...Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology.However,inheritance drives the ability to appropriately adapt to environmental stressors,and disease is the culmination of a maladaptive response.Thus "pure" genetic and "pure" xenobiotic liver diseases are modified by each other and other factors,identified or unknown.The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes.This exercise is not to argue that all liver diseases have an environmental component,but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility.This review also discusses key new tools and approaches that will likely be critical to address this question in the future.Taken together,identifying the key gaps in our understanding is critical for the field to move forward,or at the very least to "know what we don't know."展开更多
BACKGROUND Primary biliary cholangitis(PBC)is a chronic progressive liver disease of unknown aetiology characterised by immune-mediated destruction of small and medium-sized intrahepatic bile ducts.There are few well-...BACKGROUND Primary biliary cholangitis(PBC)is a chronic progressive liver disease of unknown aetiology characterised by immune-mediated destruction of small and medium-sized intrahepatic bile ducts.There are few well-established risk factors and epidemiological studies are needed to further evaluate the pathogenesis of the disease.AIM To evaluate the relationship between alcohol intake,smoking and marijuana use with PBC development.METHODS We conducted a prevalent case control study of 200 cases and 200 age(within a five year age band)and sex-matched controls,identified from the Victorian PBC prevalence study.We assessed lifetime alcohol intake and smoking behaviour(both tobacco and marijuana)prior to PBC onset and used conditional logistic regression for analyses.RESULTS Alcohol intake consistently showed a dose-dependent inverse association with case status,and this was most substantial for 21-30 years and 31-40 years(Ptrend<0.001).Smoking was associated with PBC,with a stronger association with a longer duration of smoking[e.g.,adjusted OR 2.27(95%CI:1.12-4.62)for those who had smoked for 20-35 years].There was no association between marijuana use and PBC.CONCLUSION Alcohol appears to have an inverse relationship with PBC.Smoking has been confirmed as an environmental risk factor for PBC.There was no association between marijuana use and PBC.展开更多
Autoantibody(AAb)detection has become one of the standards of diagnosis for autoimmune liver disease(AILD),and some AAbs have become specific biomarkers of AILD.In addition,AAbs can be detected in patients with non-AI...Autoantibody(AAb)detection has become one of the standards of diagnosis for autoimmune liver disease(AILD),and some AAbs have become specific biomarkers of AILD.In addition,AAbs can be detected in patients with non-AILDs,such as viral hepatitis and alcoholic liver disease.However,the distribution characteristics and pathogenic mechanisms of AAbs in patients with non-AILD are unclear.This article summarizes the characteristics of AAbs in several common clinical chronic liver diseases(CLDs)and discusses the value of AAb analysis in CLD.展开更多
Microbial cells significantly outnumber human cells in the body,and the microbial flora at mucosal sites are shaped by environmental factors and,less intuitively,act on host immune responses,as demonstrated by experim...Microbial cells significantly outnumber human cells in the body,and the microbial flora at mucosal sites are shaped by environmental factors and,less intuitively,act on host immune responses,as demonstrated by experimental data in germ-free and gnotobiotic studies.Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown,as observed in rheumatic fever triggered by Streptococci via molecular mimicry,epitope spread and bystander effects.The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases,including rheumatoid arthritis,type 1 diabetes,multiple sclerosis and autoimmune liver disease.It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena.In fact,there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity,and microbial therapeutics is being investigated to prevent or halt autoimmune diseases.As a putative mechanism,it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens,giving rise to the differentiation of autoreactive Th17 cells and other T helper cells.This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity,with an emphasis on how dysbiosis may influence systemic autoimmunity.In particular,a gut–liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm,considering its anatomic and physiological connections.展开更多
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),causing coronavirus disease 2019(COVID-19),can trigger autoimmunity in genetically predisposed individuals through hyperstimulation of immune response and molecular mimicry.Here we summarise the current knowledge about autoimmune liver diseases(AILDs)and SARS-CoV-2,focusing on:(1)The risk of SARS-CoV-2 infection and the course of COVID-19 in patients affected by AILDs;(2)the role of SARS-CoV-2 in inducing liver damage and triggering AILDs;and(3)the ability of vaccines against SARS-CoV-2 to induce autoimmune responses in the liver.Data derived from the literature suggest that patients with AILDs do not carry an increased risk of SARS-Cov-2 infection but may develop a more severe course of COVID-19 if on treatment with steroids or thiopurine.Although SARSCoV-2 infection can lead to the development of several autoimmune diseases,few reports correlate it to the appearance of de novo manifestation of immunemediated liver diseases such as autoimmune hepatitis(AIH),primary biliary cholangitis(PBC)or AIH/PBC overlap syndrome.Different case series of an AIHlike syndrome with a good prognosis after SARS-CoV-2 vaccination have been described.Although the causal link between SARS-CoV-2 vaccines and AIH cannot be definitively established,these reports suggest that this association could be more than coincidental.
基金Natural Science and Technology Major Project of Fujian Province,No.2021D033Natural Science Foundation of Shanghai,No.20ZR1410900+1 种基金Medical Innovation Project of Fujian Province,No.2022CXB020National Science and Technology Major Project,No.2017ZX 10203202-003-002.
文摘BACKGROUND Noninvasive methods have been developed to detect fibrosis in many liver diseases due to the limits of liver biopsy.However,previous studies have focused primarily on chronic viral hepatitis and nonalcoholic fatty liver disease.The diagnostic value of transient elastography for autoimmune liver diseases(AILDs)is worth studying.AIM To compare the diagnostic accuracy of imaging techniques with serum biomarkers of fibrosis in AILD.METHODS The PubMed,Cochrane Library and EMBASE databases were searched.Studies evaluating the efficacy of noninvasive methods in the diagnosis of AILDs[autoimmune hepatitis(AIH),primary biliary cholangitis(PBC)and primary sclerosing cholangitis(PSC)]were included.The summary area under the receiver operating characteristic curve(AUROC),diagnostic odds ratio,sensitivity and specificity were used to assess the accuracy of these noninvasive methods for staging fibrosis.RESULTS A total of 60 articles were included in this study,and the number of patients with AIH,PBC and PSC was 1594,3126 and 501,respectively.The summary AUROC of transient elastography in the diagnosis of significant fibrosis,advanced fibrosis and cirrhosis in patients with AIH were 0.84,0.88 and 0.90,respectively,while those in patients with PBC were 0.93,0.93 and 0.91,respectively.The AUROC of cirrhosis for patients with PSC was 0.95.However,other noninvasive indices(aspartate aminotransferase to platelet ratio index,aspartate aminotransferase/alanine aminotransferase ratio,fibrosis-4 index)had corresponding AUROCs less than 0.80.CONCLUSION Transient elastography exerts better diagnostic accuracy in AILD patients,especially in PBC patients.The appropriate cutoff values for staging advanced fibrosis and cirrhosis ranged from 9.6 to 10.7 and 14.4 to 16.9 KPa for PBC patients.
基金Supported by National Natural Science Foundation of China,No.81470842 and No.81770572.
文摘BACKGROUND Hepatic steatosis commonly occurs in some chronic liver diseases and may affect disease progression.AIM To investigate the performance of controlled attenuation parameter(CAP)for the diagnosis of hepatic steatosis in patients with autoimmune liver diseases(AILDs).METHODS Patients who were suspected of having AILDs and underwent liver biopsy were consistently enrolled.Liver stiffness measurement(LSM)and CAP were performed by transient elastography.The area under the receiver operating characteristic(AUROC)curve was used to evaluate the performance of CAP for diagnosing hepatic steatosis compared with biopsy.RESULTS Among 190 patients with biopsy-proven hepatic steatosis,69 were diagnosed with autoimmune hepatitis(AIH),18 with primary biliary cholangitis(PBC),and 27 with AIH-PBC overlap syndrome.The AUROCs of CAP for the diagnosis of steatosis in AILDS were 0.878(0.791-0.965)for S1,0.764(0.676-0.853)for S2,and 0.821(0.716-0.926)for S3.The CAP value was significantly related to hepatic steatosis grade(P<0.001).Among 69 patients with AIH,the median CAP score was 205.63±47.36 dB/m for S0,258.41±42.83 dB/m for S1,293.00±37.18 dB/m for S2,and 313.60±27.89 dB/m for S3.Compared with patients with nonalcoholic fatty liver disease(NAFLD)presenting with autoimmune markers,patients with AIH concomitant with NAFLD were much older and had higher serum IgG levels and LSM values.CONCLUSION CAP can be used as a noninvasive diagnostic method to evaluate hepatic steatosis in patients with AILDs.Determination of LSM combined with CAP may help to identify patients with AIH concomitant with NAFLD from those with NAFLD with autoimmune phenomena.
文摘More than 90%of cases of hepatocellular carcinoma(HCC)occurs in patients with cirrhosis,of which hepatitis B virus and hepatitis C virus are the leading causes,while the tumor less frequently arises in autoimmune liver diseases.Advances in understanding tumor immunity have led to a major shift in the treatment of HCC,with the emergence of immunotherapy where therapeutic agents are used to target immune cells rather than cancer cells.Regulatory T cells(Tregs)are the most abundant suppressive cells in the tumor microenvironment and their presence has been correlated with tumor progression,invasiveness,as well as metastasis.Tregs are characterized by the expression of the transcription factor Foxp3 and various mechanisms ranging from cell-to-cell contact to secretion of inhibitory molecules have been implicated in their function.Notably,Tregs amply express checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4 and programmed cell-death 1 receptor and therefore represent a direct target of immune checkpoint inhibitor(ICI)immunotherapy.Taking into consideration the critical role of Tregs in maintenance of immune homeostasis as well as avoidance of autoimmunity,it is plausible that targeting of Tregs by ICI immunotherapy results in the development of immune-related adverse events(irAEs).Since the use of ICI becomes common in oncology,with an increasing number of new ICI currently under clinical trials for cancer treatment,the occurrence of irAEs is expected to dramatically rise.Herein,we review the current literature focusing on the role of Tregs in HCC evolution taking into account their opposite etiological function in viral and autoimmune chronic liver disease,and we discuss their involvement in irAEs due to the new immunotherapies.
文摘AIM To determine the diagnostic accuracy of two-dimensional shear wave elastography(2D-SWE) for the noninvasive assessment of liver fibrosis in patients with autoimmune liver diseases(AILD) using liver biopsy as the reference standard.METHODS Patients with AILD who underwent liver biopsy and 2D-SWE were consecutively enrolled. Receiver operating characteristic(ROC) curves were constructed to assess the overall accuracy and to identify optimal cut-off values.RESULTS The characteristics of the diagnostic performance were determined for 114 patients with AILD. The areas under the ROC curves for significant fibrosis, severe fibrosis, and cirrhosis were 0.85, 0.85, and 0.86, respectively, and the optimal cut-off values associated with significant fibrosis(≥ F2), severe fibrosis(≥ F3), and cirrhosis(F4) were 9.7 k Pa, 13.2 k Pa and 16.3 k Pa, respectively. 2D-SWE showed sensitivity values of 81.7% for significant fibrosis, 83.0% for severe fibrosis,and 87.0% for cirrhosis, and the respective specificity values were 81.3%, 74.6%, and 80.2%. The overall concordance rate of the liver stiffness measurements obtained using 2D-SWE vs fibrosis stages was 53.5%.CONCLUSION2D-SWE showed promising diagnostic performance for assessing liver fibrosis stages and exhibited high cut-off values in patients with AILD. Low overall concordance rate was observed in the liver stiffness measurements obtained using 2D-SWE vs fibrosis stages.
文摘Systemic rheumatic diseases(SRDs)are chronic,inflammatory,autoimmune disorders with the presence of autoantibodies that may affect any organ or system.Liver dysfunction in SRDs can be associated with prescribed drugs,viral hepatitis,alternative hepatic comorbidities and coexisting autoimmune liver diseases(AILDs),requiring an exclusion of secondary conditions before considering liver involvement.The patterns of overlap diseases depend predominantly on genetic determinants with common susceptible loci widely distributing in both disorders.In AILDs,it is important to identify the overlapping SRDs at an early stage since such a coexistence may influence the disease course and prognosis.Commonly co-occurring SRDs in AILDs are Sjögren syndrome(SS),rheumatoid arthritis(RA)or systemic lupus erythematosus(SLE)in autoimmune hepatitis(AIH),and SS,RA or systemic sclerosis in primary biliary cholangitis.Owing to different disease complications and therapies,it is imperative to differentiate between SLE liver involvement and SLE-AIH overlap disease.Therapeutic options can be personalized to control coexisting conditions of liver autoimmunity and rheumatic manifestations in AILD-SRD overlap diseases.The collaboration between hepatologists and rheumatologists can lead to significant advances in managing such a complex scenario.In this review,we provide a comprehensive overview on coexisting AILDs in different SRDs and the therapeutic approach in managing these overlap diseases.
文摘Intestinal homeostasis depends on complex interactions between the gut microbiota and host immune system.Emerging evidence indicates that the intestinal microbiota is a key player in autoimmune liver disease(AILD).Autoimmune hepatitis,primary biliary cholangitis,primary sclerosing cholangitis,and IgG4-related sclerosing cholangitis have been linked to gut dysbiosis.Diverse mechanisms contribute to disturbances in intestinal homeostasis in AILD.Bacterial translocation and molecular mimicry can lead to hepatic inflammation and immune activation.Additionally,the gut and liver are continuously exposed to microbial metabolic products,mediating variable effects on liver immune pathologies.Importantly,microbiota-specific or associated immune responses,either hepatic or systemic,are abnormal in AILD.Comprehensive knowledge about host-microbiota interactions,included but not limited to this review,facilitates novel clinical practice from a microbiome-based perspective.However,many challenges and controversies remain in the microbiota field of AILD,and there is an urgent need for future investigations.
文摘The coronavirus disease 2019(COVID-19)pandemic has caused changes in the global health system,causing significant setbacks in healthcare systems worldwide.This pandemic has also shown resilience,flexibility,and creativity in reacting to the tragedy.The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection targets most of the respiratory tract,resulting in a severe sickness called acute respiratory distress syndrome that may be fatal in some individuals.Although the lung is the primary organ targeted by COVID-19 viruses,the clinical aspect of the disease is varied and ranges from asymptomatic to respiratory failure.However,due to an unorganized immune response and several affected mechanisms,the liver may also experience liver cell injury,ischemic liver dysfunction,and drug-induced liver injury,which can result in respiratory failure because of the immune system’s disordered response and other compromised processes that can end in multisystem organ failure.Patients with liver cirrhosis or those who have impaired immune systems may be more likely than other groups to experience worse results from the SARS-CoV-2 infection.We thus intend to examine the pathogenesis,current therapy,and consequences of liver damage concerning COVID-19.
文摘The liver is the front line organ of the immune system.The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens.This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens,such as food antigens or pathogens.As an immune active organ,the liver functions as a gatekeeping barrier from the outside world,and it can create a rapid and strong immune response,under unfavorable conditions.However,the liver's assumed immune status is anti-inflammatory or immuno-tolerant.Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance.The anatomical structure of the liver can facilitate the preparation of lymphocytes,modulate the immune response against hepatotropic pathogens,and contribute to some of its unique immunological properties,particularly its capacity to induce antigen-specific tolerance.Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane,circulating lymphocytes can closely contact with antigens,displayed by endothelial cells,Kupffer cells,and dendritic cells while passing through the sinusoids.Loss of immune tolerance,leading to an autoaggressive immune response in the liver,if not controlled,can lead to the induction of autoimmune or autoinflammatory diseases.This review mentions the unique features of liver immunity,and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.
基金Supported by the Tianqing Liver Disease Research Foundation,China Foundation for Hepatitis Prevention and Control,No.TQGB20150026Kejiaoxingwei Project of Suzhou,No.KJXW2016004
文摘AIM To investigate the levels, ratios, and clinical significance of T helper 17(Th17) cells and regulatory T(Treg) cells in the peripheral blood of patients with autoimmune liver disease(AILD). METHODS F o r t y-t w o A I L D p a t i e n t s w e r e i n c l u d e d i n t h e experimental group(group E), and 11 healthy subjects were recruited as the control group(group C). Flow cytometry was performed to determine the percentages of Th17 and Treg cells in peripheral blood lymphocytes. Furthermore, a range of biochemical indices was measured simultaneously in the blood of group E patients. RESULTS The percentage of Th17 cells and the Th17/Treg ratio were higher in group E than in group C(P < 0.01), whereas the percentage of Tregs was lower in the group E patients(P < 0.05). Patients in group E who were admitted with AILD in the active stage showed significantly higher Th17 percentages and Th17/Treg ratios than those measured in patients with AILD in remission(P < 0.05). In addition, among patients with AILD in the active stage, individuals that remained unhealed after hospitalization showed significantly higher baseline values of the Th17 percentage and the Th17/Treg ratio than those detected in patients who improved after treatment(P < 0.05). The results suggested that imbalance in the Th17/Treg ratio plays an important role in the pathogenesis and development of AILD.CONCLUSION A high Th17/Treg ratio appears to predict poor shortterm prognosis in patients with AILD in the active stage.
基金Supported by the National Science and Technology Major Project of China,No.2018ZX10302206 and No.2017ZX10202203-007-010。
文摘γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity.Based on the composition of T cell receptor and the cytokines produced,γδT cells can be divided into diverse subsets that may be present at different locations,including the liver,epithelial layer of the gut,the dermis and so on.Many of these cells perform specific functions in liver diseases,such as viral hepatitis,autoimmune liver diseases,non-alcoholic fatty liver disease,liver cirrhosis and liver cancers.In this review,we discuss the distribution,subsets,functions ofγδT cells and the relationship between the microbiota andγδT cells in common hepatic diseases.AsγδT cells have been used to cure hematological and solid tumors,we are interested inγδT cell-based immunotherapies to treat liver diseases.
基金Supported by Shanghai Hospital Development Commission,No.SHDC2020CR1037Bthe National Key R&D Program of China,No.2017YFC0908100+7 种基金the National Science and Technology Major Project,No.2018ZX10302206,2018ZX10723203 and 2017ZX10202202Shanghai Municipal Education Commission-Guofeng Clinical Medicine Grant,No.20152213the National Natural Science Foundation of China,No.82170629,81930061,81900579,81970550,82070613,82070650,and 81972265Chongqing Natural Science Foundation,No.CSTC2019jcyj-zdxmX0004Beijing Municipal Science&Technology Commission,No.Z191100006619033Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program,No.2017BT01S131the Foundation for Innovative Research Groups of Hubei Provincial Natural Science Foundation,No.2018CFA031Guangdong Basic and Applied Basic Research Foundation,No.2020A1515010052.
文摘BACKGROUND Autoimmune liver disease(AILD)has been considered a relatively uncommon disease in China,epidemiological data for AILD in patients with cirrhosis and acute decompensation(AD)is sparse.AIM To investigate the prevalence,outcome and risk factors for AILD in cirrhotic patients complicated with AD in China.METHODS We collected data from patients with cirrhosis and AD from two prospective,multicenter cohorts in hepatitis B virus endemic areas.Patients were regularly followed up at the end of 28-d,90-d and 365-d,or until death or liver transplantation(LT).The primary outcome in this study was 90-d LTfree mortality.Acute-on-chronic liver failure(ACLF)was assessed on admission and during 28-d hospitalization,according to the diagnostic criteria of the European Association for the Study of the Liver(EASL).Risk factors for death were analyzed with logistic regression model.RESULTS In patients with cirrhosis and AD,the overall prevalence of AILD was 9.3%(242/2597).Prevalence of ACLF was significantly lower in AILD cases(14%)than those with all etiology groups with cirrhosis and AD(22.8%)(P<0.001).Among 242 enrolled AILD patients,the prevalence rates of primary biliary cirrhosis(PBC),autoimmune hepatitis(AIH)and PBC-AIH overlap syndrome(PBC/AIH)were 50.8%,28.5%and 12.0%,respectively.In ACLF patients,the proportions of PBC,AIH and PBC/AIH were 41.2%,29.4% and 20.6%.28-d and 90-d mortality were 43.8% and 80.0% in AILD-related ACLF.The etiology of AILD had no significant impact on 28-d,90-d or 365-d LTfree mortality in patients with cirrhosis and AD in both univariate and multivariate analysis.Total bilirubin(TB),hepatic encephalopathy(HE)and blood urea nitrogen(BUN)were independent risk factors for 90-d LT-free mortality in multivariate analysis.The development of ACLF during hospitalization only independently correlated to TB and international normalized ratio.CONCLUSION AILD was not rare in hospitalized patients with cirrhosis and AD in China,among which PBC was the most common etiology.90-d LT-free mortality were independently associated with TB,HE and BUN.
文摘BACKGROUND Previous reports showed some beneficial effect of oral vancomycin treatment(OVT)in children with primary sclerosing cholangitis;conversely,the experience in patients with other autoimmune liver diseases(AILD),including autoimmune hepatitis(AIH)and autoimmune sclerosing cholangitis(ASC),is scant.AIM To assess the response to immunosuppressive treatment(IS)and to OVT in children diagnosed with AILD.METHODS Retrospective study of children diagnosed with AIH(normal biliary tree at cholangiography)and ASC(abnormal biliary tree at cholangiography)in the last 10 years.All underwent standard immunosuppressive therapy(IS),but nonresponders received also OVT.Biochemical remission[normal aspartate aminotransferase(AST)]and immunological remission(normal IgG and negative autoantibodies)rates and Sclerosing Cholangitis Outcomes in Pediatrics(SCOPE)index were assessed and compared during the follow up.RESULTS 75 children were included[69%female,median age 10.5 years(5.6-13.4 years),AIH=54,ASC=21].Sixty-three patients(84%,AIH=52,ASC=11)were treated with standard IS and 61 achieved biochemical remission,whereas 12 not responding to IS[16%,F=75%,median age 13.5 years,(12.2-15.7),10 with ASC]required OVT and 8 achieved biochemical remission.Overall OVT increased the biochemical remission rate of the whole group of AILD patients from 81%(61/75)to 92%(69/75).Median values of AST,alanine aminotransferase(ALT)and gamma-glutamyl transferase(GGT)decreased significantly after OVT start(P<0.05).Complete normalization of livers enzymes(AST,ALT and GGT)was observed in 6/12 patients(50%).Decrease in SCOPE index score was reported in 5/12 patients(42%).At last follow up(median of 4.4 years,range 0.6-13.8 years)all 75 patients are alive,6(8%,1 with ASC)successfully discontinued medications,1(with ASC)required liver transplantation.CONCLUSION Children with AIH and ASC respond well to IS treatment.OVT may represent a valuable treatment option to achieve biochemical remission in patients not responding to standard IS.These promising preliminary results suggest that a prospective study is indicated to define the efficacy of OVT in AILD.
基金This study was supported in part by the following grants:NHLBI(HL079584,HL080499,HL089920,HL110488,HL128014,and HL132500)NCI(CA213022),NIA(AG047776),NSFC(31870897),and NSFC(81900387).Dr.M.H.Zou is an eminent scholar of the Georgia Research Alliance.
文摘Regulatory T cells(Treg cells)are crucial for maintaining immune tolerance.Compromising the regulatory function of Treg cells can lead to autoimmune liver disease.However,how Treg cell function is regulated has not been fully clarified.Here,we report that mice with AMP-activated protein kinase alpha 1(AMPKα1)globally knocked out spontaneously develop immune-mediated liver injury,with massive lymphocyte infiltration in the liver,elevated serum alanine aminotransferase levels,and greater production of autoantibodies.Both transplantation of wild-type bone marrow and adoptive transfer of wild-type Treg cells can prevent liver injury in AMPKα1-KO mice.In addition,Treg cell-specific AMPKα1-KO mice display histological features similar to those associated with autoimmune liver disease,greater production of autoantibodies,and hyperactivation of CD4^(+)T cells.AMPKα1 deficiency significantly impairs Treg cell suppressive function but does not affect Treg cell differentiation or proliferation.Furthermore,AMPK is activated upon T cell receptor(TCR)stimulation,which triggers Foxp3 phosphorylation,suppressing Foxp3 ubiquitination and proteasomal degradation.Importantly,the frequency of Treg cells and the phosphorylation levels of AMPK at T172 in circulating blood are significantly lower in patients with autoimmune liver diseases.Conclusion:Our data suggest that AMPK maintains the immunosuppressive function of Treg cells and confers protection against autoimmune liver disease.
基金supported in part by the National Natural Science Foundation of China(grants#81830016,81771732,and 81620108002 to X.M.,#81922010 and 81873561 to R.T.)supported in part by services provided by the NIH centers P30 DK120515 and P50 AA011999+1 种基金supported by the excellence initiative VASCage(Centre for Promoting Vascular Health in the Ageing Community)R8fD K-Centre(COMET program-Competence Centers for Excellent Technologies)funded by the Austrian Ministry for Transport,Innovation and Technology,the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol,Salzburg and Vienna.
文摘The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology.The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota.The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens.Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases.Of immense importance is the step from high-throughput sequencing(correlation)to mechanistic studies(causality)and therapeutic intervention.Here,we review the gut microbiota,liver immunology,and the interaction between the gut and liver.In addition,the impairment in the gut-liver axis found in various liver diseases is reviewed here,with an emphasis on alcohol-associated liver disease(ALD),nonalcoholic fatty liver disease(NAFLD),and autoimmune liver disease(AILD).On the basis of growing evidence from these preclinical studies,we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.
基金supported by funding from the German Research Foundation(DFG),Collaborative Research grants within the CRC841(SFB841:"Liver inflammation:Infection,immune regulation und consequences"),projects B01 to A.K.H.and G.T.,B09 to L.D.the Clinical Research Group KF0306("Primary Sclerosing Cholangitis"),project 04 to G.T.
文摘The liver is an important immunological organ that controls systemic tolerance.The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance.Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment,which Is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes.In response to pathogens or autoantigens,tolerance is disrupted by unknown mechanisms.Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties.The presentation of microbial and endogenous lipid-,metabolite-and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance.Perturbation of this balance results in autoimmune liver diseases,such as autoimmune hepatitis,primary biliary cholangitis,and primary sclerosing cholangitis.Although the exact etiologies of these autoimmune liver diseases are unknown,it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids,as well as alterations in bile acid composition,may result in changes in effector cell activation and polarization and may reduce or impair protective antiinflammatory regulatory T and B cell responses.Additionally,the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different(non)immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance.Here,we summarize emerging aspects of antigen presentation,autoantibody production,and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.
基金Supported, in part, by grants from NIH (R01 AA021978, P30 DK120531, and R21 ES031531, USA)。
文摘Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology.However,inheritance drives the ability to appropriately adapt to environmental stressors,and disease is the culmination of a maladaptive response.Thus "pure" genetic and "pure" xenobiotic liver diseases are modified by each other and other factors,identified or unknown.The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes.This exercise is not to argue that all liver diseases have an environmental component,but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility.This review also discusses key new tools and approaches that will likely be critical to address this question in the future.Taken together,identifying the key gaps in our understanding is critical for the field to move forward,or at the very least to "know what we don't know."
文摘BACKGROUND Primary biliary cholangitis(PBC)is a chronic progressive liver disease of unknown aetiology characterised by immune-mediated destruction of small and medium-sized intrahepatic bile ducts.There are few well-established risk factors and epidemiological studies are needed to further evaluate the pathogenesis of the disease.AIM To evaluate the relationship between alcohol intake,smoking and marijuana use with PBC development.METHODS We conducted a prevalent case control study of 200 cases and 200 age(within a five year age band)and sex-matched controls,identified from the Victorian PBC prevalence study.We assessed lifetime alcohol intake and smoking behaviour(both tobacco and marijuana)prior to PBC onset and used conditional logistic regression for analyses.RESULTS Alcohol intake consistently showed a dose-dependent inverse association with case status,and this was most substantial for 21-30 years and 31-40 years(Ptrend<0.001).Smoking was associated with PBC,with a stronger association with a longer duration of smoking[e.g.,adjusted OR 2.27(95%CI:1.12-4.62)for those who had smoked for 20-35 years].There was no association between marijuana use and PBC.CONCLUSION Alcohol appears to have an inverse relationship with PBC.Smoking has been confirmed as an environmental risk factor for PBC.There was no association between marijuana use and PBC.
基金Talent Development Plan for Beijing High-level Public Health Technical Personnel Project,Grant/Award Number:2022-2-014。
文摘Autoantibody(AAb)detection has become one of the standards of diagnosis for autoimmune liver disease(AILD),and some AAbs have become specific biomarkers of AILD.In addition,AAbs can be detected in patients with non-AILDs,such as viral hepatitis and alcoholic liver disease.However,the distribution characteristics and pathogenic mechanisms of AAbs in patients with non-AILD are unclear.This article summarizes the characteristics of AAbs in several common clinical chronic liver diseases(CLDs)and discusses the value of AAb analysis in CLD.
基金This work was supported by awards from the National Nature Science Foundation of China(#81771732 and 81620108002 to Xiong Ma,#81400608 to Ruqi Tang).
文摘Microbial cells significantly outnumber human cells in the body,and the microbial flora at mucosal sites are shaped by environmental factors and,less intuitively,act on host immune responses,as demonstrated by experimental data in germ-free and gnotobiotic studies.Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown,as observed in rheumatic fever triggered by Streptococci via molecular mimicry,epitope spread and bystander effects.The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases,including rheumatoid arthritis,type 1 diabetes,multiple sclerosis and autoimmune liver disease.It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena.In fact,there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity,and microbial therapeutics is being investigated to prevent or halt autoimmune diseases.As a putative mechanism,it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens,giving rise to the differentiation of autoreactive Th17 cells and other T helper cells.This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity,with an emphasis on how dysbiosis may influence systemic autoimmunity.In particular,a gut–liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm,considering its anatomic and physiological connections.
