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  1. Article ; Online: Introducing Molecular Chaperones into the Causality and Prospective Management of Autoimmune Hepatitis.

    Czaja, Albert J

    Digestive diseases and sciences

    2023  Volume 68, Issue 11, Page(s) 4098–4116

    Abstract: Molecular chaperones influence the immunogenicity of peptides and the activation of effector T cells, and their pathogenic roles in autoimmune hepatitis are unclear. Heat shock proteins are pivotal in the processing and presentation of peptides that ... ...

    Abstract Molecular chaperones influence the immunogenicity of peptides and the activation of effector T cells, and their pathogenic roles in autoimmune hepatitis are unclear. Heat shock proteins are pivotal in the processing and presentation of peptides that activate CD8
    Language English
    Publishing date 2023-09-27
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 304250-9
    ISSN 1573-2568 ; 0163-2116
    ISSN (online) 1573-2568
    ISSN 0163-2116
    DOI 10.1007/s10620-023-08118-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis.

    Czaja, Albert J

    Digestive diseases and sciences

    2023  Volume 68, Issue 7, Page(s) 2824–2842

    Abstract: Molecular mimicry between foreign and self-antigens has been implicated as a cause of autoimmune hepatitis in experimental models and cross-reacting antibodies in patients. This review describes the experimental and clinical evidence for molecular ... ...

    Abstract Molecular mimicry between foreign and self-antigens has been implicated as a cause of autoimmune hepatitis in experimental models and cross-reacting antibodies in patients. This review describes the experimental and clinical evidence for molecular mimicry as a cause of autoimmune hepatitis, indicates the limitations and uncertainties of this premise, and encourages investigations that assess diverse environmental antigens as sources of disease-relevant molecular mimics. Pertinent articles were identified in PubMed using multiple search phrases. Several pathogens have linear or conformational epitopes that mimic the self-antigens of autoimmune hepatitis. The occurrence of an acute immune-mediated hepatitis after vaccination for severe acute respiratory syndrome (SARS)-associated coronavirus 2 (SARS-CoV-2) has suggested that vaccine-induced peptides may mimic disease-relevant tissue antigens. The intestinal microbiome is an under-evaluated source of gut-derived antigens that could also engage in molecular mimicry. Chaperone molecules may enhance the pathogenicity of molecular mimics, and they warrant investigation. Molecular mimics of immune dominant epitopes within cytochrome P450 IID6, the autoantigen most closely associated with autoimmune hepatitis, should be sought in diverse environmental antigens and assessed for pathogenicity. Avoidance strategies, dietary adjustments, vaccine improvement, and targeted manipulation of the intestinal microbiota may emerge as therapeutic possibilities. In conclusion, molecular mimicry may be a missing causality of autoimmune hepatitis. Molecular mimics of key immune dominant epitopes of disease-specific antigens must be sought in diverse environmental antigens. The ubiquity of molecular mimicry compels rigorous assessments of peptide mimics for immunogenicity and pathogenicity in experimental models. Molecular mimicry may complement epigenetic modifications as causative mechanisms of autoimmune hepatitis.
    MeSH term(s) Humans ; Hepatitis, Autoimmune ; Molecular Mimicry ; COVID-19 ; SARS-CoV-2 ; Autoantigens ; Epitopes ; Peptides
    Chemical Substances Autoantigens ; Epitopes ; Peptides
    Language English
    Publishing date 2023-05-09
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 304250-9
    ISSN 1573-2568 ; 0163-2116
    ISSN (online) 1573-2568
    ISSN 0163-2116
    DOI 10.1007/s10620-023-07967-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Epigenetic Aspects and Prospects in Autoimmune Hepatitis.

    Czaja, Albert J

    Frontiers in immunology

    2022  Volume 13, Page(s) 921765

    Abstract: The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic ... ...

    Abstract The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4
    MeSH term(s) Epigenesis, Genetic ; Fibrosis ; Hepatitis, Autoimmune ; Humans ; Liver Cirrhosis/metabolism ; MicroRNAs/genetics ; MicroRNAs/therapeutic use
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2022-06-30
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2022.921765
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Examining micro-ribonucleic acids as diagnostic and therapeutic prospects in autoimmune hepatitis.

    Czaja, Albert J

    Expert review of clinical immunology

    2022  Volume 18, Issue 6, Page(s) 591–607

    Abstract: Introduction: Micro-ribonucleic acids modulate the immune response by affecting the post-transcriptional expression of genes that influence the proliferation and function of activated immune cells, including regulatory T cells. Individual expressions or ...

    Abstract Introduction: Micro-ribonucleic acids modulate the immune response by affecting the post-transcriptional expression of genes that influence the proliferation and function of activated immune cells, including regulatory T cells. Individual expressions or patterns in peripheral blood and liver tissue may have diagnostic value, reflect treatment response, or become therapeutic targets. The goals of this review are to present the properties and actions of micro-ribonucleic acids, indicate the key individual expressions in autoimmune hepatitis, and describe prospective clinical applications in diagnosis and management.
    Areas covered: Abstracts were identified in PubMed using the search words "microRNAs," "microRNAs in liver disease," and "microRNAs in autoimmune hepatitis." The number of abstracts reviewed exceeded 2000, and the number of full-length articles reviewed was 108.
    Expert opinion: Individual micro-ribonucleic acids, miR-21, miR-122, and miR-155, have been associated with biochemical severity, histological grade of inflammation, and pivotal pathogenic mechanisms in autoimmune hepatitis. Antisense oligonucleotides that down-regulate deleterious individual gene expressions, engineered molecules that impair targeting of gene products, and drugs that non-selectively up-regulate the biogenesis of potentially deficient gene regulators are feasible treatment options. Micro-ribonucleic acids constitute an under-evaluated area in autoimmune hepatitis that promises to improve diagnosis, pathogenic concepts, and therapy.
    MeSH term(s) Hepatitis, Autoimmune/diagnosis ; Hepatitis, Autoimmune/genetics ; Hepatitis, Autoimmune/therapy ; Humans ; MicroRNAs/genetics ; Prospective Studies ; T-Lymphocytes, Regulatory
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2022-05-12
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2274260-8
    ISSN 1744-8409 ; 1744-666X
    ISSN (online) 1744-8409
    ISSN 1744-666X
    DOI 10.1080/1744666X.2022.2074839
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Missing Causality and Heritability of Autoimmune Hepatitis.

    Czaja, Albert J

    Digestive diseases and sciences

    2022  Volume 68, Issue 4, Page(s) 1585–1604

    Abstract: Background: Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies.: Aims: ... ...

    Abstract Background: Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies.
    Aims: Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential.
    Methods: English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed.
    Results: Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape.
    Conclusions: Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
    MeSH term(s) Humans ; Hepatitis, Autoimmune ; Epigenesis, Genetic ; Phenotype
    Language English
    Publishing date 2022-10-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 304250-9
    ISSN 1573-2568 ; 0163-2116
    ISSN (online) 1573-2568
    ISSN 0163-2116
    DOI 10.1007/s10620-022-07728-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Advancing Biologic Therapy for Refractory Autoimmune Hepatitis.

    Czaja, Albert J

    Digestive diseases and sciences

    2022  Volume 67, Issue 11, Page(s) 4979–5005

    Abstract: Biologic agents may satisfy an unmet clinical need for treatment of refractory autoimmune hepatitis. The goals of this review are to present the types and results of biologic therapy for refractory autoimmune hepatitis, indicate opportunities to improve ... ...

    Abstract Biologic agents may satisfy an unmet clinical need for treatment of refractory autoimmune hepatitis. The goals of this review are to present the types and results of biologic therapy for refractory autoimmune hepatitis, indicate opportunities to improve and expand biologic treatment, and encourage comparative clinical trials. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Rituximab (monoclonal antibodies against CD20 on B cells), infliximab (monoclonal antibodies against tumor necrosis factor-alpha), low-dose recombinant interleukin 2 (regulatory T cell promoter), and belimumab (monoclonal antibodies against B cell activating factor) have induced laboratory improvement in small cohorts with refractory autoimmune hepatitis. Ianalumab (monoclonal antibodies against the receptor for B cell activating factor) is in clinical trial. These agents target critical pathogenic pathways, but they may also have serious side effects. Blockade of the B cell activating factor or its receptors may disrupt pivotal B and T cell responses, and recombinant interleukin 2 complexed with certain interleukin 2 antibodies may selectively expand the regulatory T cell population. A proliferation-inducing ligand that enhances T cell proliferation and survival is an unevaluated, potentially pivotal, therapeutic target. Fully human antibodies, expanded target options, improved targeting precision, more effective delivery systems, and biosimilar agents promise to improve efficacy, safety, and accessibility. In conclusion, biologic agents target key pathogenic pathways in autoimmune hepatitis, and early experiences in refractory disease encourage clarification of the preferred target, rigorous clinical trial, and comparative evaluations.
    MeSH term(s) Humans ; Hepatitis, Autoimmune/drug therapy ; B-Cell Activating Factor ; Rituximab/therapeutic use ; Interleukin-2/therapeutic use ; Infliximab/therapeutic use ; Tumor Necrosis Factor-alpha ; Biosimilar Pharmaceuticals/therapeutic use ; Antibodies, Monoclonal/therapeutic use ; Biological Therapy
    Chemical Substances B-Cell Activating Factor ; Rituximab (4F4X42SYQ6) ; Interleukin-2 ; Infliximab (B72HH48FLU) ; Tumor Necrosis Factor-alpha ; Biosimilar Pharmaceuticals ; Antibodies, Monoclonal
    Language English
    Publishing date 2022-02-11
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 304250-9
    ISSN 1573-2568 ; 0163-2116
    ISSN (online) 1573-2568
    ISSN 0163-2116
    DOI 10.1007/s10620-021-07378-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Immune Inhibitory Properties and Therapeutic Prospects of Transforming Growth Factor-Beta and Interleukin 10 in Autoimmune Hepatitis.

    Czaja, Albert J

    Digestive diseases and sciences

    2021  Volume 67, Issue 4, Page(s) 1163–1186

    Abstract: Transforming growth factor-beta and interleukin 10 have diverse immune inhibitory properties that have restored homeostatic defense mechanisms in experimental models of autoimmune disease. The goals of this review are to describe the actions of each ... ...

    Abstract Transforming growth factor-beta and interleukin 10 have diverse immune inhibitory properties that have restored homeostatic defense mechanisms in experimental models of autoimmune disease. The goals of this review are to describe the actions of each cytokine, review their investigational use in animal models and patients, and indicate their prospects as interventions in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Transforming growth factor-beta expands the natural and inducible populations of regulatory T cells, limits the proliferation of natural killer cells, suppresses the activation of naïve CD8
    MeSH term(s) Animals ; CD8-Positive T-Lymphocytes ; Hepatitis, Autoimmune/drug therapy ; Humans ; Interleukin-10 ; Interleukin-2/therapeutic use ; Transforming Growth Factor beta ; Transforming Growth Factors/therapeutic use
    Chemical Substances Interleukin-2 ; Transforming Growth Factor beta ; Interleukin-10 (130068-27-8) ; Transforming Growth Factors (76057-06-2)
    Language English
    Publishing date 2021-04-09
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 304250-9
    ISSN 1573-2568 ; 0163-2116
    ISSN (online) 1573-2568
    ISSN 0163-2116
    DOI 10.1007/s10620-021-06968-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Review article: targeting the B cell activation system in autoimmune hepatitis.

    Czaja, Albert J

    Alimentary pharmacology & therapeutics

    2021  Volume 54, Issue 7, Page(s) 902–922

    Abstract: Background: The B cell activation system, consisting of B cell activating factor and a proliferation-inducing ligand, may have pathogenic effects in autoimmune hepatitis.: Aims: To describe the biological actions of the B cell activation system, ... ...

    Abstract Background: The B cell activation system, consisting of B cell activating factor and a proliferation-inducing ligand, may have pathogenic effects in autoimmune hepatitis.
    Aims: To describe the biological actions of the B cell activation system, indicate its possible role in autoimmune diseases, and evaluate its prospects as a therapeutic target in autoimmune hepatitis METHODS: English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed.
    Results: The B cell activating factor is crucial for the maturation and survival of B cells, and it can co-stimulate T cell activation, proliferation, and survival. It can also modulate the immune response by inducing interleukin 10 production by regulatory B cells. A proliferation-inducing ligand modulates and diversifies the antibody response by inducing class-switch recombination in B cells. It can also increase the proliferation, survival, and antigen activation of T cells. These immune stimulatory actions can be modulated by inducing proliferation of regulatory T cells. The B cell activation system has been implicated in diverse autoimmune diseases, and therapeutic blockade is a management strategy now being evaluated in autoimmune hepatitis.
    Conclusions: The B cell activation system has profound effects on B and T cell function in autoimmune diseases. Blockade therapy is being actively evaluated in autoimmune hepatitis. Clarification of the critical pathogenic components of the B cell activation system will improve the targeting, efficacy, and safety of blockade therapy in this disease.
    MeSH term(s) B-Lymphocytes ; Hepatitis, Autoimmune/drug therapy ; Humans ; T-Lymphocytes, Regulatory
    Language English
    Publishing date 2021-09-10
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 639012-2
    ISSN 1365-2036 ; 0269-2813 ; 0953-0673
    ISSN (online) 1365-2036
    ISSN 0269-2813 ; 0953-0673
    DOI 10.1111/apt.16574
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease.

    Czaja, Albert J

    World journal of gastroenterology

    2021  Volume 27, Issue 25, Page(s) 3705–3733

    Abstract: Mucosal-associated invariant T (MAIT) cells have been described in liver and non-liver diseases, and they have been ascribed antimicrobial, immune regulatory, protective, and pathogenic roles. The goals of this review are to describe their biological ... ...

    Abstract Mucosal-associated invariant T (MAIT) cells have been described in liver and non-liver diseases, and they have been ascribed antimicrobial, immune regulatory, protective, and pathogenic roles. The 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 implications. English abstracts were identified in PubMed by multiple search terms, and bibliographies were developed. MAIT cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory cytokines. Diverse pro-inflammatory, anti-inflammatory, and immune regulatory cytokines are released; infected cells are eliminated; and memory cells emerge. Circulating MAIT cells are hyper-activated, immune exhausted, dysfunctional, and depleted in chronic liver disease. This phenotype lacks disease-specificity, and it does not predict the biological effects. MAIT cells have presumed protective actions in chronic viral hepatitis, alcoholic hepatitis, non-alcoholic fatty liver disease, primary sclerosing cholangitis, and decompensated cirrhosis. They have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary cholangitis. Local factors in the hepatic microenvironment (cytokines, bile acids, gut-derived bacterial antigens, and metabolic by-products) may modulate their response in individual diseases. Investigational manipulations of function are warranted to establish an association with disease severity and outcome. In conclusion, MAIT cells constitute a disease-nonspecific, immune response to chronic liver inflammation and infection. Their 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.
    MeSH term(s) Cytokines ; Humans ; Liver Cirrhosis, Biliary ; Mucosal-Associated Invariant T Cells ; Non-alcoholic Fatty Liver Disease
    Chemical Substances Cytokines
    Language English
    Publishing date 2021-07-28
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2185929-2
    ISSN 2219-2840 ; 1007-9327
    ISSN (online) 2219-2840
    ISSN 1007-9327
    DOI 10.3748/wjg.v27.i25.3705
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Autoimmune Hepatitis: Surviving Crises of Doubt and Elimination.

    Czaja, Albert J

    Clinical liver disease

    2020  Volume 15, Issue Suppl 1, Page(s) S72–S81

    Language English
    Publishing date 2020-03-02
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2657644-2
    ISSN 2046-2484
    ISSN 2046-2484
    DOI 10.1002/cld.917
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