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Examining pathogenic concepts of autoimmune hepatitis for cues to future investigations and interventions

World journal of Gastroenterology 2019年第45期25卷 6579-6606页

作者： albert j czaja Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine and Science

BACKGROUND Multiple pathogenic mechanisms have been implicated in autoimmune hepatitis,but they have not fully explained susceptibility,triggering events,and maintenance or escalation of the ***,they have not identified a critical defect that can be *** goals of this review are to examine the diverse pathogenic mechanisms that have been considered in autoimmune hepatitis,indicate investigational opportunities to validate their contribution,and suggest interventions that might evolve to modify their *** abstracts were identified in PubMed by multiple search *** length articles were selected for review,and secondary and tertiary bibliographies were *** and epigenetic factors can affect susceptibility by influencing the expression of immune regulatory *** dysfunction,possibly related to deficient production of programmed cell death protein-1,can allow autoreactive T cells to escape deletion,and alterations in the intestinal microbiome may help overcome immune tolerance and affect gender *** factors may trigger the disease or induce epigenetic changes in gene *** mimicry,epitope spread,bystander activation,neo-antigen production,lymphocytic polyspecificity,and disturbances in immune inhibitory mechanisms may maintain or escalate the *** that modify epigenetic effects on gene expression,alter intestinal dysbiosis,eliminate deleterious environmental factors,and target critical pathogenic mechanisms are therapeutic possibilities that might reduce risk,individualize management,and improve *** conclusion,diverse pathogenic mechanisms have been implicated in autoimmune hepatitis,and they may identify a critical factor or sequence that can be validated and used to direct future management and preventive strategies.

关键词： Autoimmune hepatitis Pathogenesis Epigenetics Molecular mimicry Epitope spread Intestinal microbiome

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Hepatic inflammation and progressive liver fibrosis in chronic liver disease

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World journal of Gastroenterology 2014年第10期20卷 2515-2532页

作者： albert j czaja Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester MN 55905 United States

Chronic liver inflammation drives hepatic fibrosis,and current immunosuppressive,anti-inflammatory,and anti-viral therapies can weaken this *** fibrosis is reversed,stabilized,or prevented in 57%-79%of patients by conventional treatment regimens,mainly by their anti-inflammatory ***,however,are commonly incomplete and inconsistently *** fibrotic mechanisms associated with liver inflammation have been clarified,and anti-fibrotic agents promise to improve outcomes as adjunctive *** C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within *** can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen ***-oxidants(Nacetylcysteine,S-adenosyl-L-methionine,and vitamin E)and angiotensin inhibitors(losartin)have had antifibrotic actions in preliminary human studies,and they may emerge as supplemental ***-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.

关键词： Inflammation Fibrosis Cirrhosis Treatment Anti-oxidants Angiotensin receptors Investigational drugs

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Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis

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World journal of Gastroenterology 2016年第42期22卷 9257-9278页

作者： albert j czaja Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine

The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora(dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens(molecular mimicry). Activated gutderived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.

关键词： Intestinal microbiome Inflammasomes Autoimmune hepatitis Dysbiosis Toll-like receptors

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Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease

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World journal of Gastroenterology 2021年第25期27卷 3705-3733页

作者： albert j czaja Department of Medicine Mayo Clinic College of Medicine and ScienceRochesterMN 55905United States

Mucosal-associated invariant T(MAIT)cells have been described in liver and nonliver diseases,and they have been ascribed antimicrobial,immune regulatory,protective,and pathogenic *** goals of this review are to describe their biological properties,indicate their involvement in chronic liver disease,and encourage investigations that clarify their actions and therapeutic *** abstracts were identified in PubMed by multiple search terms,and bibliographies were *** cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory *** pro-inflammatory,anti-inflammatory,and immune regulatory cytokines are released;infected cells are eliminated;and memory cells *** MAIT cells are hyper-activated,immune exhausted,dysfunctional,and depleted in chronic liver *** phenotype lacks disease-specificity,and it does not predict the biological *** cells have presumed protective actions in chronic viral hepatitis,alcoholic hepatitis,non-alcoholic fatty liver disease,primary sclerosing cholangitis,and decompensated *** have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary *** factors in the hepatic microenvironment(cytokines,bile acids,gut-derived bacterial antigens,and metabolic by-products)may modulate their response in individual *** manipulations of function are warranted to establish an association with disease severity and *** conclusion,MAIT cells constitute a disease-nonspecific,immune response to chronic liver inflammation and *** pathological role has been deduced from their deficiencies during active liver disease,and future investigations must clarify this role,link it to outcome,and explore therapeutic interventions.

关键词： Innate-like lymphocytes Antimicrobial Immune regulatory Pathogenic Mucosal-associated invariant T cell

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Difficult treatment decisions in autoimmune hepatitis

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World journal of Gastroenterology 2010年第8期16卷 934-947页

作者： albert j czaja Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine

Treatment decisions in autoimmune hepatitis are complicated by the diversity of its clinical presentations,uncertainties about its natural history,evolving opinions regarding treatment end points,varied nature of refractory disease,and plethora of alternative immu-nosuppressive agents. The goals of this article are to review the difficult treatment decisions and to provide the bases for making sound therapeutic judgments. The English literature on the treatment problems in au-toimmune hepatitis were identifi ed by Medline search up to October 2009 and 32 years of personal experi-ence. Autoimmune hepatitis may have an acute severe presentation,mild in? ammatory activity,lack autoan-tibodies,exhibit atypical histological changes (centri-lobular zone 3 necrosis or bile duct injury),or have variant features reminiscent of another disease (overlap syndrome). Corticosteroid therapy must be instituted early,applied despite the absence of symptoms,or modified in an individualized fashion. Pursuit of normal liver tests and tissue is the ideal treatment end point,but this objective must be tempered against the risk of side effects. Relapse after treatment withdrawal requires long-term maintenance therapy,preferably with azathioprine. Treatment failure or an incomplete response warrants salvage therapy that can include conventional medications in modified dose or empiricaltherapies with calcineurin inhibitors or mycophenolate mofetil. Liver transplantation supersedes empirical drug therapy in decompensated patients. Elderly and pregnant patients warrant treatment modifications. Difficult treatment decisions in autoimmune hepatitis can be simplified by recognizing its diverse manifestations and individualizing treatment,pursuing realistic goals,applying appropriate salvage regimens,and identifying problematic patients early.

关键词： Autoimmune hepatitis Fulminant hepatitis Salvage therapy Treatment end points

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Non-classical phenotypes of autoimmune hepatitis and advances in diagnosis and treatment

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World journal of Gastroenterology 2009年第19期15卷 2314-2328页

作者： albert j czaja Yusuf Bayraktar Division of Gastroenterology and Hepatology Mayo Clinic College of MedicineRochesterMinnesotaUnited States and the Department of GastroenterologyHacettepe University School of MedicineAnkara 06100Turkey

Non-classical manifestations of autoimmune hepatitis can delay diagnosis and treatment. Our aims were to describe the clinical phenotypes that can confound the diagnosis, detail scoring systems that can ensure their recognition, and outline advances in treatment that can improve their outcome. Prime source and review articles in English were selected throuqh Medline from 1970-2008 and assimilated into personal libraries spanning 32 years. Acute severe or asymptomatic presentations and atypical histological findings,including centrilobular zone 3 necrosis and concurrent bile duct changes, are compatible with the diagnosis. Cholangiographic abnormalities may be present in children and adults with the disease, and autoimmune hepatitis must be considered in patients without autoantibodies or with antimitochondrial antibodies and no other cholestatic features. Asymptomatic patients frequently become symptomatic; mild disease can progress; and there are no confident indices that justify withholding treatment. Two diagnostic scoring systems with complementary virtues have been developed to evaluate patients with confusing features. Normal liver tests and tissue constitute the optimal end point of treatment, and the first relapse is an indication for long- term azathioprine therapy. Cyclosporine, tacrolimus and mycophenolate mofetil are promising salvage therapies,and budesonide with azathioprine may be a superior frontline treatment. We conclude that the non-classical phenotypes of autoimmune hepatitis can be recognized promptly, diagnosed accurately, and treated effectively.

关键词： Non-classical phenotypes Scoring systems Treatment strategies

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Magnetic resonance elastography is accurate in detecting advanced fibrosis in autoimmune hepatitis

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World journal of Gastroenterology 2017年第5期23卷 859-868页

作者： jin Wang Neera Malik Meng Yin Thomas C Smyrk albert j czaja Richard L Ehman Sudhakar K Venkatesh Department of Radiology Mayo Clinic College of MedicineMayo Clinic Department of Radiology the Third Affiliated HospitalSun Yat-Sen University Laboratory Medicine and Pathology Mayo Clinic College of MedicineMayo Clinic Department of Gastroenterology and Hepatology Mayo Clinic College of MedicineMayo Clinic

AIM To assess the value of magnetic resonance elastography (MRE) in detecting advanced fibrosis/cirrhosis in autoimmune hepatitis (AIH). METHODS In this retrospective study, 36 patients (19 treated and 17 untreated) with histologically confirmed AIH and liver biopsy performed within 3 mo of MRE were identified at a tertiary care referral center. Liver stiffness (LS) with MRE was calculated by a radiologist, and inflammation grade and fibrosis stage in liver biopsy was assessed by a pathologist in a blinded fashion. Two radiologists evaluated morphological features of cirrhosis on conventional magnetic resonance imaging (MRI). Accuracy of MRE was compared to laboratory markers and MRI for detection of advanced fibrosis/cirrhosis. RESULTS Liver fibrosis stages of 0, 1, 2, 3 and 4 were present in 4, 6, 7, 6 and 13 patients respectively. There were no significant differences in distribution of fibrosis stage and inflammation grade between treated and untreated patient groups. LS with MRE demonstrated stronger correlation with liver fibrosis stage in comparison to laboratory markers for chronic liver disease (r = 0.88 vs -0.48-0.70). A trend of decreased mean LS in treated patients compared to untreated patients was observed (3.7 kPa vs 3.84 kPa) but was not statistically significant. MRE had an accuracy/sensitivity/specificity/positive predictive value/negative predictive value of 0.97/90%/100%/100%/90% and 0.98/92.3%/96%/92.3%/96% for detection of advanced fibrosis and cirrhosis, respectively. The performance of MRE was significantly better than laboratory tests for detection of advanced fibrosis (0.97 vs 0.53-0.80, p < 0.01), and cirrhosis (0.98 vs 0.58-0.80, p < 0.01) and better than conventional MRI for diagnosis of cirrhosis (0.98 vs 0.78, p = 0.002). CONCLUSION MRE is a promising modality for detection of advanced fibrosis and cirrhosis in patients with AIH with superior diagnostic accuracy compared to laboratory assessment and MRI.

关键词： autoimmune hepatitis advanced fibrosis magnetic resonance elastography liver stiffness cirrhosis

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Genetic distinctions between autoimmune hepatitis in Italy and North America

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World journal of Gastroenterology 2005年第12期11卷 1862-1866页

作者： Paolo Muratori albert j.czaja Luigi Muratori Georgios Pappas Silvana Maccariello Fabio Cassani Alessandro Granito Rodolfo Ferrari Vilma Mantovani Marco Lenzi Francesco B.Bianchi Department of Internal Medicine Division of Gastroenterology and Hepatology Laboratorio Centralizzato Settore Genetica

AIM: Our goals were to analyze the known genetic predispositions for autoimmune hepatitis (AIH) in AIH Italian population and to compare them with North American counterparts. METHODS: Human leukocyte antigens (HLA) B8, C7, DR3, DR4, DR7, DR11, DR13, DQ2 and the B8-DR3-DQ2 phenotype were determined by microlymphocytotoxicity and polymerase chain reaction in 74 Italian patients (57 with type 1 and 17 with type 2 AIH) and 149 North American patients with type 1 AIH, and in adequate controls. RESULTS: B8-DR3-DQ2 occurred more frequently in Italian patients with type 1 AIH than in Italian controls (30% vs 7%, P<0.0001), but less frequently than in North American counterparts (30% vs 48%, P= 0.02). DR4 occurred less frequently in Italian patients with type 1 AIH (23% vs 43%, P= 0.01) and in controls (16% vs 34%, P= 0.0003) than in North American counterparts. No differences were found in alleles' frequency between type 1 and type 2 Italian AIH patients. DR11 had a frequency lower in type 1 Italian AIH patients than controls (17% vs 35%, P= 0.01). CONCLUSION: HLA DR4 is not associated with AIH in Italy. The known HLA risk factors for AIH occur similarly in Italian patients with type 1 and type 2 AIH, and they are less frequent than in North American patients. B8-DR3-DQ2 is the predominant phenotype of type 1 AIH also in Italy, and HLA DR11 may be a regionally distinctive protective factor against type 1 AIH.

关键词： Type 1 autoimmune hepatitis Type 2 autoimmune hepatitis Human leukocyte antigen

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Recent Trends in Satellite-Derived Chlorophyll and Aerosol Optical Depth Together with Simulated Dimethylsulfide in the Eastern China Marginal Seas

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journal of Ocean University of China 2022年第2期21卷 486-498页

作者： QU Bo GABRIC albert j. School of Science Nantong UniversityNantong 266000China School of Environment and Science Griffith UniversityBrisbaneQLDAustralia

The biogenic compound dimethylsulfide(DMS)produced by a range of marine biota is the major natural source of re-duced sulfur to the atmosphere and plays a major role in the formation and evolution of aerosols,potentially affecting *** spatio-temporal distribution of satellite-derived chlorophyll_a(CHL)and aerosol optical depth(AOD)for the recent years(2011-2019)in the Eastern China Marginal Seas(ECMS)(25°-40°N,120°-130°E)are *** seasonal CHL peaks occurred during late April and the CHL distribution displays a clear zonal *** CHL was also observed along the northern and western coastlines during summer and winter *** analysis shows that mean CHL decreases by about 10%over the 9-year study period,while AOD was higher in south and lower in north during summertime.A genetic algorithm technique is used to calibrate the key model parameters and simulations are carried out for 2015,a year when field data was *** simulation results show that DMS seawater concentration ranges from 1.56 to 5.88 nmol L^(−1) with a mean value of 2.76 nmol L^(−1).DMS sea-air flux ranges from 2.66 to 5.00mmol m^(−2) d^(−1) with mean of 3.80mmol m^(−2) d^(−1).Positive correlations of about 0.5 between CHL and AOD were found in the study region,with higher correlations along the coasts of jiangsu and Zhejiang *** elevated CHL concentration along the west coast is correlated with increased sea-water concentrations of DMS in the *** results suggest a possible influ-ence of DMS-derived aerosol in the local ECMS atmosphere,especially along the western coastline of ECMS.

关键词： dimethylsulfide sea-to-air flux chlorophyll-a aerosol optical depth biogeochemical model Eastern China Marginal Seas

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Using genetic algorithms to calibrate a dimethylsulfide production model in the Arctic Ocean

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Chinese journal of Oceanology and Limnology 2010年第3期28卷 573-582页

作者：瞿波 GABRIC j.albert Nantong University Griffith University

The global climate is intimately connected to changes in the polar oceans. The variability of sea ice coverage affects deep-water formations and large-scale thermohaline circulation patterns. The polar radiative budget is sensitive to sea-ice loss and consequent surface albedo changes. Aerosols and polar cloud microphysics are crucial players in the radioactive energy balance of the Arctic Ocean. The main biogenic source of sulfate aerosols to the atmosphere above remote seas is dimethylsulfide (DMS). Recent research suggests the flux of DMS to the Arctic atmosphere may change markedly under global warming. This paper describes climate data and DMS production (based on the five years from 1998 to 2002) in the region of the Barents Sea (30–35°E and 70–80°N). A DMS model is introduced together with an updated calibration method. A genetic algorithm is used to calibrate the chlorophyll-a (CHL) measurements (based on satellite SeaWiFS data) and DMS content (determined from cruise data collected in the Arctic). Significant interannual variation of the CHL amount leads to significant interannual variability in the observed and modeled production of DMS in the study region. Strong DMS production in 1998 could have been caused by a large amount of ice algae being released in the southern region. Forcings from a general circulation model (CSIRO Mk3) were applied to the calibrated DMS model to predict the zonal mean sea-to-air flux of DMS for contemporary and enhanced greenhouse conditions at 70–80°N. It was found that significantly decreasing ice coverage, increasing sea surface temperature and decreasing mixed-layer depth could lead to annual DMS flux increases of more than 100% by the time of equivalent CO2 tripling (the year 2080). This significant perturbation in the aerosol climate could have a large impact on the regional Arctic heat budget and consequences for global warming.

关键词： Arctic Ocean dimethyl sulfide mixed-layer depth chlorophyll-a dimethyl sulfoniopropionate

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