Materiały źródłowe

• #1 Pathogenesis of autoimmune hepatitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8422914/

  Autoimmune hepatitis (AIH) is a chronic progressive liver disease whose etiology and pathogenesis are not yet clear. It is currently believed that the occurrence of AIH is closely related to genetic susceptibility and immune abnormalities, and other factors such as environment, viral infection and drugs that may cause immune dysfunction. […] Although the exact pathogenesis of AIH is still unclear, there are many theories, and the continuous in-depth research on its pathogenesis has led to development in treatment of AIH. […] The pathogenesis of AIH still needs further research.

• #2 Autoimmmune hepatitis | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-021-00768-8

  Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.

• #3 Autoimmune Hepatitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459186/

  Autoimmune hepatitis refers to chronic and progressive inflammation of the liver from an unknown cause. The proposed mechanism for the development of autoimmune hepatitis is thought to be the interplay of genetic predisposition, an environmental trigger, and failure of the native immune system resulting in chronic inflammation of hepatocytes and subsequent fibrosis of the liver. […] The current proposition for pathogenesis is thought to be secondary to a failure of immune tolerance in a genetically susceptible individual leading to a T-cell mediated inflammation caused by various environmental triggers. Common triggers include infections, medications, and toxins. Certain human leukocyte antigen (HLA) haplotypes are more susceptible to the development of autoimmune hepatitis. Susceptible alleles are different in different ethnic groups. Among White North Americans and Northern Europeans, susceptible alleles are located on the short arm of chromosome 6, specifically within the region of DRB-1. Nitrofurantoin and minocycline are well-documented culprits of drug-induced autoimmune hepatitis. Tumor necrosis factor-alpha drugs have been more recently linked to autoimmune hepatitis.

• #4 Autoimmune Hepatitis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172356-overview

  Autoimmune hepatitis is a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis. Progressive fibrosis may lead to cirrhosis. […] The proposed pathogenesis of autoimmune hepatitis involves the combination of genetic predisposition and environmental triggers. The genetic predisposition may relate to several defects in immunologic control of autoreactivity. An environmental agent may trigger the autoimmune response against liver antigens, causing necroinflammatory liver damage, fibrosis, and, eventually, cirrhosis, if left untreated. […] Genetic susceptibility to developing autoimmune hepatitis has been associated with the human leukocyte antigen (HLA) haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients.

• #5 Autoimmmune hepatitis | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-021-00768-8

  Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.

• #6 Final Diagnosis — Case 554

  https://path.upmc.edu/cases/case554/dx.html

  Over three quarters of AIH cases arise in patients with a well characterized genetic predisposition. In the Caucasian population presence of the HLA-DRB1*0301 and HLA-DRB1*0401 haplotypes confers a significantly increased risk of AIH. Moreover, the DRB1*0301 allele was found to be associated with earlier disease onset and higher frequency of treatment failure. Another allele, HLA-DRB1*1301 could be detected in 45% of North-American AIH patients, who were negative for both DR3 and DR4. On the other hand, patients with an HLA-B8 allele tend to have a more aggressive disease course. In the Italian population HLA-B8-DR3-DQ2, in Japan HLA-DRB1*0405 are the most frequent AIH associated haplotypes. […] The most popular models of AIH pathogenesis are built around the „molecular mimicry” hypothesis. Molecular mimicry describes the phenomena when antibodies directed against foreign antigens cross-react with self-antigens resulting in an autoimmune disorder. The structural similarities found between the epitopes of CYP2D6 and herpes simplex virus as well as between FTCD and herpes virus type 6 indicate that antigen cross-reactions may have a significant role in AIH pathogenesis. Interestingly, anti-LKM antibodies seen in Type 2 AIH are also found in HCV infection, and sometimes anti-LKM-1 positive patients cross-react with the NS3 and NS5a viral proteins. Another intriguing evidence in favor of the „molecular mimicry hypothesis is that immunization of mice with the human CYP2D6 and FTCD alloantigens can be successfully used to generate murine models of AIH.

• #7 Autoimmmune hepatitis | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-021-00768-8

  Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.

• #8 The progress of autoimmune hepatitis research and future challenges

  https://www.degruyter.com/document/doi/10.1515/med-2023-0823/html?lang=en

  AIH causes autoimmune intolerance, resulting in autoimmune cells attacking hepatocytes. However, AIH pathogenesis, which could involve genetic predisposition, environmental factors, and immune system dysregulation, remains incompletely elucidated. […] AIH is a polygenic disease of unknown etiology, and genetic factors can influence the disease progression and clinical phenotype of AIH. AIH patients are associated with extrahepatic autoimmune disease, and about 40% have an autoimmune disease history in the family. Genome-wide association studies have revealed that the human leukocyte antigen (HLA) locus and some non-HLA loci are primarily associated with the AIH region. AIH genetic susceptibility is related to HLA region genes on the short arm of chromosome 6, particularly with DRB1 allelic variants. The diagnostic effectiveness of HLA susceptibility alleles in identifying individuals with AIH is widely recognized, leading to their inclusion in the AIH diagnostic criteria. MHC class II HLA DRB1 alleles DRB1*0301 and DRB1*0401 encode amino acid sequences that render humans in Europe and North America more susceptible to AIH-1. DRB1*15:01 can reduce the risk of AIH1 in the population. Besides, DRB1*03, DRB1*07, and DQB1*02:01 will make the population more susceptible to AIH-2. Other genes also affect AIH development since some patients with the disease do not carry HLA alleles. In addition to non-HLA genes having immunological significance, the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene + 49A/G genotype was significantly correlated with AIH susceptibility. The CTLA-4 gene, located on chromosome 2q33, includes a single base exchange polymorphism in exon 1, in which there is a guanine replaced by adenine at position 49, resulting in the expressed protein There is a threonine instead of alanine. A recent investigation obtained the genotypes of 155 persons diagnosed with AIH who belong to the Nordic Caucasian population and 102 healthy individuals from the same racial background. The expression of each genotype was AA = 50/155 patients vs 51/102 controls; AG = 84/155 patients vs 38/102 controls; GG = 21/155 patients vs 13/102 controls, x2 = 8.94, P = 0.011). In addition, there is a synergistic effect between CTLA-4 + 49A/G and DRB1*03:01 on AIH-1 susceptibility. A recent study showed that the GG genotype of CTLA-4 CT 60 accounted for 36.2% of AIH patients, significantly higher than that of the control group (10.0%). The strength of the correlation between the two variables, as measured by Cramers V, was determined to be 0.341, indicating a moderate level of correlation. The bias-corrected Cramers V demonstrated a moderate correlation, exhibiting a correlation coefficient of 0.322. The CTLA-4 GG genotype significantly increases the risk of AIH-1 when patients have HLA DRB1*0301 in their genotype. In Tunisian patients, the CTLA-4 + 49 position GG genotype was also positively associated with AIH susceptibility. In addition, tumor necrosis factor–inducible protein 3 (TNFAIP3) is a genetically encoded ubiquitinating enzyme whose rs10499194 T allele and CT genotype are associated with an elevated risk of developing AIH. Thus, the rs10499194 polymorphism is an AIH locus for candidate susceptibility. Patients in the Japanese population who had detrimental mutations in TNFAIP3 had an increased risk of cirrhosis-related AIH. The receptor for Fas was found to be significantly elevated in lymphocytes from AIH patients. Furthermore, the surface expression of Fas in CD4+ and CD8+ T lymphocyte subsets was significantly higher in AIH patients compared with normal subjects. Expanded Fas+ T cells also reflect the presence of persistent antigen-specific or non-specific activation in the body and abnormalities in the peripheral loss of activated lymphocytes. A Japanese study observed that Fas polymorphisms and AIH development were strongly correlated with genetic factors. And the Fas-670A allele carriers showed an elevated risk of developing AIH. Inflammatory cytokines are also involved in AIH development. For instance, the IL-4-590 C/T polymorphism and the IL-4-33 TT genotype increase AIH susceptibility. In vivo intervention with recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) can reduce the secretion of TNF-alpha and interleukin-17 (IL-17) and the infiltration of inflammatory cells in the liver thereby inhibiting ConA-induced hepatitis. CCN1 promotes inflammation by upregulating IL-6 production in ConA mice through the 61/PI3K/Akt/NF-B pathway. Recently, miRNAs have also demonstrated a crucial impact on AIH development. A study comparing serum miRNAs showed significant differences between healthy individuals and AIH patients. Compared with controls, serum levels of miR-29a were decreased, miR-378, let-7b, miR-122 and miR-192 were increased, and miR-574-3p, miR-193a-5p and miR-148a were unchanged. This indicates that the combination can be utilized to differentiate between people with AIH. Furthermore, a substantial correlation was found between miR-557 and a higher chance of recurrence. Additionally, it might also distinguish AIH patients from hepatitis C (HCV) patients, primary biliary hepatitis patients with cholangitis, and non-alcoholic steatohepatitis patients. The expression level of miR-155 was significantly elevated in liver specimens of AIH patients but was reduced in peripheral blood mononuclear cells. In the CoA model, the level of miR-223 in Kupffer cells of mice with early liver damage was significantly increased, and transfection of miR-223 mimics could inhibit the activation of Kupffer cells after Con A stimulation.

• #9 The progress of autoimmune hepatitis research and future challenges

  https://www.degruyter.com/document/doi/10.1515/med-2023-0823/html?lang=en

  AIH causes autoimmune intolerance, resulting in autoimmune cells attacking hepatocytes. However, AIH pathogenesis, which could involve genetic predisposition, environmental factors, and immune system dysregulation, remains incompletely elucidated. […] AIH is a polygenic disease of unknown etiology, and genetic factors can influence the disease progression and clinical phenotype of AIH. AIH patients are associated with extrahepatic autoimmune disease, and about 40% have an autoimmune disease history in the family. Genome-wide association studies have revealed that the human leukocyte antigen (HLA) locus and some non-HLA loci are primarily associated with the AIH region. AIH genetic susceptibility is related to HLA region genes on the short arm of chromosome 6, particularly with DRB1 allelic variants. The diagnostic effectiveness of HLA susceptibility alleles in identifying individuals with AIH is widely recognized, leading to their inclusion in the AIH diagnostic criteria. MHC class II HLA DRB1 alleles DRB1*0301 and DRB1*0401 encode amino acid sequences that render humans in Europe and North America more susceptible to AIH-1. DRB1*15:01 can reduce the risk of AIH1 in the population. Besides, DRB1*03, DRB1*07, and DQB1*02:01 will make the population more susceptible to AIH-2. Other genes also affect AIH development since some patients with the disease do not carry HLA alleles. In addition to non-HLA genes having immunological significance, the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene + 49A/G genotype was significantly correlated with AIH susceptibility. The CTLA-4 gene, located on chromosome 2q33, includes a single base exchange polymorphism in exon 1, in which there is a guanine replaced by adenine at position 49, resulting in the expressed protein There is a threonine instead of alanine. A recent investigation obtained the genotypes of 155 persons diagnosed with AIH who belong to the Nordic Caucasian population and 102 healthy individuals from the same racial background. The expression of each genotype was AA = 50/155 patients vs 51/102 controls; AG = 84/155 patients vs 38/102 controls; GG = 21/155 patients vs 13/102 controls, x2 = 8.94, P = 0.011). In addition, there is a synergistic effect between CTLA-4 + 49A/G and DRB1*03:01 on AIH-1 susceptibility. A recent study showed that the GG genotype of CTLA-4 CT 60 accounted for 36.2% of AIH patients, significantly higher than that of the control group (10.0%). The strength of the correlation between the two variables, as measured by Cramers V, was determined to be 0.341, indicating a moderate level of correlation. The bias-corrected Cramers V demonstrated a moderate correlation, exhibiting a correlation coefficient of 0.322. The CTLA-4 GG genotype significantly increases the risk of AIH-1 when patients have HLA DRB1*0301 in their genotype. In Tunisian patients, the CTLA-4 + 49 position GG genotype was also positively associated with AIH susceptibility. In addition, tumor necrosis factor–inducible protein 3 (TNFAIP3) is a genetically encoded ubiquitinating enzyme whose rs10499194 T allele and CT genotype are associated with an elevated risk of developing AIH. Thus, the rs10499194 polymorphism is an AIH locus for candidate susceptibility. Patients in the Japanese population who had detrimental mutations in TNFAIP3 had an increased risk of cirrhosis-related AIH. The receptor for Fas was found to be significantly elevated in lymphocytes from AIH patients. Furthermore, the surface expression of Fas in CD4+ and CD8+ T lymphocyte subsets was significantly higher in AIH patients compared with normal subjects. Expanded Fas+ T cells also reflect the presence of persistent antigen-specific or non-specific activation in the body and abnormalities in the peripheral loss of activated lymphocytes. A Japanese study observed that Fas polymorphisms and AIH development were strongly correlated with genetic factors. And the Fas-670A allele carriers showed an elevated risk of developing AIH. Inflammatory cytokines are also involved in AIH development. For instance, the IL-4-590 C/T polymorphism and the IL-4-33 TT genotype increase AIH susceptibility. In vivo intervention with recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) can reduce the secretion of TNF-alpha and interleukin-17 (IL-17) and the infiltration of inflammatory cells in the liver thereby inhibiting ConA-induced hepatitis. CCN1 promotes inflammation by upregulating IL-6 production in ConA mice through the 61/PI3K/Akt/NF-B pathway. Recently, miRNAs have also demonstrated a crucial impact on AIH development. A study comparing serum miRNAs showed significant differences between healthy individuals and AIH patients. Compared with controls, serum levels of miR-29a were decreased, miR-378, let-7b, miR-122 and miR-192 were increased, and miR-574-3p, miR-193a-5p and miR-148a were unchanged. This indicates that the combination can be utilized to differentiate between people with AIH. Furthermore, a substantial correlation was found between miR-557 and a higher chance of recurrence. Additionally, it might also distinguish AIH patients from hepatitis C (HCV) patients, primary biliary hepatitis patients with cholangitis, and non-alcoholic steatohepatitis patients. The expression level of miR-155 was significantly elevated in liver specimens of AIH patients but was reduced in peripheral blood mononuclear cells. In the CoA model, the level of miR-223 in Kupffer cells of mice with early liver damage was significantly increased, and transfection of miR-223 mimics could inhibit the activation of Kupffer cells after Con A stimulation.

• #10 The progress of autoimmune hepatitis research and future challenges

  https://www.degruyter.com/document/doi/10.1515/med-2023-0823/html?lang=en

  AIH causes autoimmune intolerance, resulting in autoimmune cells attacking hepatocytes. However, AIH pathogenesis, which could involve genetic predisposition, environmental factors, and immune system dysregulation, remains incompletely elucidated. […] AIH is a polygenic disease of unknown etiology, and genetic factors can influence the disease progression and clinical phenotype of AIH. AIH patients are associated with extrahepatic autoimmune disease, and about 40% have an autoimmune disease history in the family. Genome-wide association studies have revealed that the human leukocyte antigen (HLA) locus and some non-HLA loci are primarily associated with the AIH region. AIH genetic susceptibility is related to HLA region genes on the short arm of chromosome 6, particularly with DRB1 allelic variants. The diagnostic effectiveness of HLA susceptibility alleles in identifying individuals with AIH is widely recognized, leading to their inclusion in the AIH diagnostic criteria. MHC class II HLA DRB1 alleles DRB1*0301 and DRB1*0401 encode amino acid sequences that render humans in Europe and North America more susceptible to AIH-1. DRB1*15:01 can reduce the risk of AIH1 in the population. Besides, DRB1*03, DRB1*07, and DQB1*02:01 will make the population more susceptible to AIH-2. Other genes also affect AIH development since some patients with the disease do not carry HLA alleles. In addition to non-HLA genes having immunological significance, the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene + 49A/G genotype was significantly correlated with AIH susceptibility. The CTLA-4 gene, located on chromosome 2q33, includes a single base exchange polymorphism in exon 1, in which there is a guanine replaced by adenine at position 49, resulting in the expressed protein There is a threonine instead of alanine. A recent investigation obtained the genotypes of 155 persons diagnosed with AIH who belong to the Nordic Caucasian population and 102 healthy individuals from the same racial background. The expression of each genotype was AA = 50/155 patients vs 51/102 controls; AG = 84/155 patients vs 38/102 controls; GG = 21/155 patients vs 13/102 controls, x2 = 8.94, P = 0.011). In addition, there is a synergistic effect between CTLA-4 + 49A/G and DRB1*03:01 on AIH-1 susceptibility. A recent study showed that the GG genotype of CTLA-4 CT 60 accounted for 36.2% of AIH patients, significantly higher than that of the control group (10.0%). The strength of the correlation between the two variables, as measured by Cramers V, was determined to be 0.341, indicating a moderate level of correlation. The bias-corrected Cramers V demonstrated a moderate correlation, exhibiting a correlation coefficient of 0.322. The CTLA-4 GG genotype significantly increases the risk of AIH-1 when patients have HLA DRB1*0301 in their genotype. In Tunisian patients, the CTLA-4 + 49 position GG genotype was also positively associated with AIH susceptibility. In addition, tumor necrosis factor–inducible protein 3 (TNFAIP3) is a genetically encoded ubiquitinating enzyme whose rs10499194 T allele and CT genotype are associated with an elevated risk of developing AIH. Thus, the rs10499194 polymorphism is an AIH locus for candidate susceptibility. Patients in the Japanese population who had detrimental mutations in TNFAIP3 had an increased risk of cirrhosis-related AIH. The receptor for Fas was found to be significantly elevated in lymphocytes from AIH patients. Furthermore, the surface expression of Fas in CD4+ and CD8+ T lymphocyte subsets was significantly higher in AIH patients compared with normal subjects. Expanded Fas+ T cells also reflect the presence of persistent antigen-specific or non-specific activation in the body and abnormalities in the peripheral loss of activated lymphocytes. A Japanese study observed that Fas polymorphisms and AIH development were strongly correlated with genetic factors. And the Fas-670A allele carriers showed an elevated risk of developing AIH. Inflammatory cytokines are also involved in AIH development. For instance, the IL-4-590 C/T polymorphism and the IL-4-33 TT genotype increase AIH susceptibility. In vivo intervention with recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) can reduce the secretion of TNF-alpha and interleukin-17 (IL-17) and the infiltration of inflammatory cells in the liver thereby inhibiting ConA-induced hepatitis. CCN1 promotes inflammation by upregulating IL-6 production in ConA mice through the 61/PI3K/Akt/NF-B pathway. Recently, miRNAs have also demonstrated a crucial impact on AIH development. A study comparing serum miRNAs showed significant differences between healthy individuals and AIH patients. Compared with controls, serum levels of miR-29a were decreased, miR-378, let-7b, miR-122 and miR-192 were increased, and miR-574-3p, miR-193a-5p and miR-148a were unchanged. This indicates that the combination can be utilized to differentiate between people with AIH. Furthermore, a substantial correlation was found between miR-557 and a higher chance of recurrence. Additionally, it might also distinguish AIH patients from hepatitis C (HCV) patients, primary biliary hepatitis patients with cholangitis, and non-alcoholic steatohepatitis patients. The expression level of miR-155 was significantly elevated in liver specimens of AIH patients but was reduced in peripheral blood mononuclear cells. In the CoA model, the level of miR-223 in Kupffer cells of mice with early liver damage was significantly increased, and transfection of miR-223 mimics could inhibit the activation of Kupffer cells after Con A stimulation.

• #11 Autoimmune Hepatitis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172356-overview

  Autoimmune hepatitis is a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis. Progressive fibrosis may lead to cirrhosis. […] The proposed pathogenesis of autoimmune hepatitis involves the combination of genetic predisposition and environmental triggers. The genetic predisposition may relate to several defects in immunologic control of autoreactivity. An environmental agent may trigger the autoimmune response against liver antigens, causing necroinflammatory liver damage, fibrosis, and, eventually, cirrhosis, if left untreated. […] Genetic susceptibility to developing autoimmune hepatitis has been associated with the human leukocyte antigen (HLA) haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients.

• #12 Autoimmune Hepatitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459186/

  Autoimmune hepatitis refers to chronic and progressive inflammation of the liver from an unknown cause. The proposed mechanism for the development of autoimmune hepatitis is thought to be the interplay of genetic predisposition, an environmental trigger, and failure of the native immune system resulting in chronic inflammation of hepatocytes and subsequent fibrosis of the liver. […] The current proposition for pathogenesis is thought to be secondary to a failure of immune tolerance in a genetically susceptible individual leading to a T-cell mediated inflammation caused by various environmental triggers. Common triggers include infections, medications, and toxins. Certain human leukocyte antigen (HLA) haplotypes are more susceptible to the development of autoimmune hepatitis. Susceptible alleles are different in different ethnic groups. Among White North Americans and Northern Europeans, susceptible alleles are located on the short arm of chromosome 6, specifically within the region of DRB-1. Nitrofurantoin and minocycline are well-documented culprits of drug-induced autoimmune hepatitis. Tumor necrosis factor-alpha drugs have been more recently linked to autoimmune hepatitis.

• #13 Pulsenotes | Autoimmune hepatitis

  https://app.pulsenotes.com/medicine/hepatology/notes/autoimmune-hepatitis

  A number of genetic factors have been identified as possible predisposing factors for development of AIH. These are broadly divided into human leucocyte antigen (HLA) and non-HLA loci. […] Other genes involved in immunoregulation have been implicated in development of autoimmune diseases such as AIH. These include T cell receptor CTLA-4 and the transcription factor autoimmune regulatory type 1 (AIRE-1). AIRE-1 regulates clonal deletion of autoreactive T cells (i.e. cells that attack self-antigens) that is implicated in autoimmune polyglandular syndrome type 1 (APS1). […] The majority of AIH cases have no readily identifiable precipitant. Precipitants may include herbal chemicals, drugs or viral infections. Several viruses have been implicated in triggering AIH including hepatitis A and human herpes viruses (e.g. herpes simplex, cytomegalovirus, Epstein-Barr). […] While circulating autoantibodies form the hallmark of AIH, there is little evidence to support their role in the pathogenesis.

• #14 Hepatitis – Wikipedia

  https://en.wikipedia.org/wiki/Hepatitis

  Autoimmune hepatitis is a chronic disease caused by an abnormal immune response against liver cells. The disease is thought to have a genetic predisposition as it is associated with certain human leukocyte antigens involved in the immune response. As in other autoimmune diseases, circulating auto-antibodies may be present and are helpful in diagnosis. Auto-antibodies found in patients with autoimmune hepatitis include the sensitive but less specific anti-nuclear antibody (ANA), smooth muscle antibody (SMA), and atypical perinuclear antineutrophil cytoplasmic antibody (p-ANCA). Other autoantibodies that are less common but more specific to autoimmune hepatitis are the antibodies against liver kidney microsome 1 (LKM1) and soluble liver antigen (SLA). Autoimmune hepatitis can also be triggered by drugs (such as nitrofurantoin, hydralazine, and methyldopa), after liver transplant, or by viruses (such as hepatitis A, Epstein-Barr virus, or measles).

• #15 Autoimmune Hepatitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459186/

  Autoimmune hepatitis refers to chronic and progressive inflammation of the liver from an unknown cause. The proposed mechanism for the development of autoimmune hepatitis is thought to be the interplay of genetic predisposition, an environmental trigger, and failure of the native immune system resulting in chronic inflammation of hepatocytes and subsequent fibrosis of the liver. […] The current proposition for pathogenesis is thought to be secondary to a failure of immune tolerance in a genetically susceptible individual leading to a T-cell mediated inflammation caused by various environmental triggers. Common triggers include infections, medications, and toxins. Certain human leukocyte antigen (HLA) haplotypes are more susceptible to the development of autoimmune hepatitis. Susceptible alleles are different in different ethnic groups. Among White North Americans and Northern Europeans, susceptible alleles are located on the short arm of chromosome 6, specifically within the region of DRB-1. Nitrofurantoin and minocycline are well-documented culprits of drug-induced autoimmune hepatitis. Tumor necrosis factor-alpha drugs have been more recently linked to autoimmune hepatitis.

• #16 Recent advances in the diagnosis and management of autoimmune hepatitis – Polish Archives of Internal Medicine

  https://www.mp.pl/paim/issue/article/16334/

  Autoimmune hepatitis (AIH) is an acute or chronic inflammatory disease of the liver caused by an immune response of unknown origin. It affects people from all ethnic groups irrespective of age or sex. AIH is characterized by hyperglobulinemia, presence of circulating autoantibodies, and liver inflammation. […] Even though the etiology of AIH is still not clear, there is evidence that the development of the disease is based on genetic predisposition as well as environmental and epigenetic factors. […] Exposure of genetically predisposed individuals to certain environmental factors (viruses, microbes, xenobiotics, drugs, herbal supplements) has been linked to the development of AIH. […] New data relate AIH to the gut microbiome and immune system activation through gut-liver axis signaling.

• #17 Recent advances in the diagnosis and management of autoimmune hepatitis – Polish Archives of Internal Medicine

  https://www.mp.pl/paim/issue/article/16334/

  Autoimmune hepatitis (AIH) is an acute or chronic inflammatory disease of the liver caused by an immune response of unknown origin. It affects people from all ethnic groups irrespective of age or sex. AIH is characterized by hyperglobulinemia, presence of circulating autoantibodies, and liver inflammation. […] Even though the etiology of AIH is still not clear, there is evidence that the development of the disease is based on genetic predisposition as well as environmental and epigenetic factors. […] Exposure of genetically predisposed individuals to certain environmental factors (viruses, microbes, xenobiotics, drugs, herbal supplements) has been linked to the development of AIH. […] New data relate AIH to the gut microbiome and immune system activation through gut-liver axis signaling.

• #18 Genetic risk factors for autoimmune hepatitis: implications for phenotypic heterogeneity and biomarkers for drug response | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/s40246-020-00301-4

  Autoimmune hepatitis (AIH) is a rare chronic progressive liver disease with autoimmune features. Genetic and environmental factors are involved in the pathogenesis of AIH. A genome-wide association study (GWAS) on European AIH revealed the strongest associations to be with single nucleotide variants (SNVs) in HLA. Predisposing alleles for AIH were DRB1*03:01 and DRB1*04:01 in Europeans; DRB1*04:04, DRB1*04:05, and DRB1*13:01 in Latin Americans; and DRB1*04:01 and DRB1*04:05 in Japanese. Other risk SNVs in non-HLA genes for AIH were found by a candidate gene approach, but several SNVs were confirmed in replication studies. Some genetic factors of AIH overlapped with those of other autoimmune diseases. The role of gene-environment interactions has also been predicted in autoimmune diseases. Viral infections, low levels of vitamin D, altered microbiota, exposure to sex hormones, and the administering of drugs are candidate environmental factors in an individual’s predisposition to AIH. A concordance of AIH in twins and AIH family accumulation were evident in a recent epidemiological study, and extrahepatic autoimmune diseases have been frequently observed in AIH patients, suggesting common genetic risk factors for AIH and other autoimmune diseases. Although HLA is the strongest genetic risk factor for AIH, other genetic factors associated with non-HLA genes have also been reported. The results of genetic studies might provide an explanation for the phenotypic heterogeneity of AIH and biomarkers for drug responses.

• #19 Autoimmmune hepatitis | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-021-00768-8

  Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.

• #20 Autoimmune Hepatitis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172356-overview

  Autoimmune hepatitis appears to arise a consequence of the breakdown of immune tolerance. Typically, regulatory T cells help to maintain immune homeostasis. A decrease in their number and function may permit unimpeded presentation of liver autoantigen peptides by professional antigen presenting cells (APCs) to CD4+ helper T (Th) cells. This, in turn, may stimulate naive T cells to differentiate into other T-cell lineages (eg, Th1, Th2, Th17). CD4 Th1 cells produce cytokines such as tumor necrosis factor alpha (TNF-) and interferon gamma (IFN-) that stimulate the proliferation of CK8 cytotoxic T lymphocytes (CTLs) and the activation of macrophages. CD4 Th2 cells produce cytokines such as interleukin (IL)-4, IL-5, IL-10, and IL-13 that stimulate B lymphocytes to produce immunoglobulins. Subsequent immunologic reactions ultimately lead to liver cell damage.

• #21 Autoimmmune hepatitis | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-021-00768-8

  The etiology of AIH remains unknown, while pathophysiological mechanisms and risk factors have been described and are constantly updated. […] AIH is characterized histologically by a dense infiltrate of lymphocytes, macrophages and plasma cells in the liver. Despite the presence of circulating autoantibodies and plasma cell liver infiltration, AIH is considered a T cell disease, since B cell activation is a T cell dependent event. The key pathogenic role of T cells in AIH is mirrored by the disease predisposition conferred by HLA class II polymorphisms. […] Loss of tolerance towards self-antigens associated with regulatory T cell (Tregs) dysfunction is central to AIH pathogenesis. Tregs play a central role in maintaining immune tolerance and have been extensively studied in AIH, providing solid evidence of functional and numerical impairment in this condition. In patients with AIH-1 and AIH-2, Tregs are defective in number and this reduction is more evident at diagnosis and during relapses than during drug-induced remission.

• #22 Autoimmmune hepatitis | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-021-00768-8

  The etiology of AIH remains unknown, while pathophysiological mechanisms and risk factors have been described and are constantly updated. […] AIH is characterized histologically by a dense infiltrate of lymphocytes, macrophages and plasma cells in the liver. Despite the presence of circulating autoantibodies and plasma cell liver infiltration, AIH is considered a T cell disease, since B cell activation is a T cell dependent event. The key pathogenic role of T cells in AIH is mirrored by the disease predisposition conferred by HLA class II polymorphisms. […] Loss of tolerance towards self-antigens associated with regulatory T cell (Tregs) dysfunction is central to AIH pathogenesis. Tregs play a central role in maintaining immune tolerance and have been extensively studied in AIH, providing solid evidence of functional and numerical impairment in this condition. In patients with AIH-1 and AIH-2, Tregs are defective in number and this reduction is more evident at diagnosis and during relapses than during drug-induced remission.

• #23

  https://xiahepublishing.com/2310-8819/JCTH-2013-00015

  Autoimmune hepatitis (AIH) is an important disorder that predominantly results in inflammatory liver disease in genetically predisposed women. […] Here we provide an overview of the current state of knowledge on AIH and summarize the treatment options for this serious condition in adults. We also discuss the pathogenesis of the disease as a possible consequence of autoimmunity and the breakdown of hepatic tolerance. […] The following pathogenetic model has been proposed: in a genetically predisposed host, defined environmental agent(s) catalyze(s) and trigger a series of T cell-mediated immune events directed at hepatic cellular antigens, resulting in unfettered inflammation, which ultimately culminates in fibrotic transformation of the liver, aberrant regeneration, and cirrhosis. […] A major contributor to AIH pathogenesis is the failure of immunoregulation as a result of diminished function and sheer number of Tregs, with consequent massive recruitment of inflammatory effector cells, which inflict hepatic injury.

• #24

  https://xiahepublishing.com/2310-8819/JCTH-2013-00015

  In health, immunotolerance to liver autoantigens is maintained by effective control of CD4+CD25+FOXP3+Tregs over CD4+ and CD8+ autoreactive T lymphocytes. […] The machinery enabling Tregs to modulate effector immune responses relies on the expression of CD39, an ectonucleotidase ultimately leading to the generation of immunomodulatory adenosine. […] In AIH, Tregs are numerically defective and express low levels of CD39. This results in poor generation of adenosine and ineffective control over autoreactive lymphocytes, with consequent perpetuation of hepatocyte damage. […] Treatment-induced remission of AIH is associated with restoration of Treg function. […] Natural killer T (NKT) cells may also be involved in the pathogenesis of AIH. […] The purinergic receptor P2X7 recognizes extracellular ATP, and is crucial in regulating the function of NKT cells.

• #25 Autoimmmune hepatitis | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-021-00768-8

  The involvement of Th 17, which secrete the proinflammatory cytokines IL-17, IL-22 and TNF and promote IL-6 secretion by hepatocytes, has been investigated more recently. […] Emerging data suggest that follicular T helper (TFH) cells, also known as follicular B helper T cells, are involved in the pathogenesis of AIH. […] The immune response in AIH is believed to be initiated by the presentation of self-antigenic peptides, as yet unknown, to the T cell receptor (TCR) of uncommitted naive CD4 T-helper (Th0) lymphocytes. Self-antigens of interest are CYP2D6 and FTCD in AIH-2 and human SepSecS-tRNASec complex (SEPSECS) in AIH-1, as the formers are the targets of anti-LKM1 and anti-LC1, while the latter is the target of anti-soluble liver antigen (anti-SLA).

• #26 Autoimmune hepatitis: Risk factors, pathophysiology, diagnosis an

  https://www.openaccessjournals.com/articles/autoimmune-hepatitis-risk-factors-pathophysiology-diagnosis-and-management-15645.html

  Autoimmune hepatitis is characterized as an entity of chronic hepatitis that must be distinguished from chronic viral hepatitis, drug-induced and alcohol-induced hepatitis and idiopathic chronic hepatitis. The pathogenesis of autoimmune hepatitis is very complex and includes interactions between the tolerant liver, environmental triggers, and dysregulated immunological mechanisms. […] The pathogenesis of AIH is very complex and includes interactions between the tolerant liver, environmental triggers, and dysregulated immunological mechanisms. […] The immune response in autoimmune hepatitis is likely induced by the presentation of self-antigens to uncommitted naive CD4+ T Helper cells (TH0). T cells targeting the self-epitope become primed and expand, which leads to induction and perpetuation of autoimmune-mediated liver damage. Molecular mimicry is well explained in AIH-2, in which the key target of humoral and cellular autoimmune responses has been defined as the liver enzyme Cytochrome P450 2D6 (CYP2D6), which is the target of the anti- LKM1 antibody. An amino acid sequence of CYP2D6 reveals an elevated level of homology with proteins encoded by HCV and members of the herpes virus family (for example, cytomegalovirus, EpsteinBarr virus, and herpes simplex virus).

• #27 Autoimmune Hepatitis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172356-overview

  Autoimmune hepatitis appears to arise a consequence of the breakdown of immune tolerance. Typically, regulatory T cells help to maintain immune homeostasis. A decrease in their number and function may permit unimpeded presentation of liver autoantigen peptides by professional antigen presenting cells (APCs) to CD4+ helper T (Th) cells. This, in turn, may stimulate naive T cells to differentiate into other T-cell lineages (eg, Th1, Th2, Th17). CD4 Th1 cells produce cytokines such as tumor necrosis factor alpha (TNF-) and interferon gamma (IFN-) that stimulate the proliferation of CK8 cytotoxic T lymphocytes (CTLs) and the activation of macrophages. CD4 Th2 cells produce cytokines such as interleukin (IL)-4, IL-5, IL-10, and IL-13 that stimulate B lymphocytes to produce immunoglobulins. Subsequent immunologic reactions ultimately lead to liver cell damage.

• #28 Autoimmune hepatitis: Risk factors, pathophysiology, diagnosis an

  https://www.openaccessjournals.com/articles/autoimmune-hepatitis-risk-factors-pathophysiology-diagnosis-and-management-15645.html

  The immune response in AIH is probably induced by the presentation of self-antigens to uncommitted naive CD4+ T helper (TH0) cells. Antigen-Presenting Cells (APCs), such as Dendritic Cells (DCs), macrophages, and B cells, are included in the processing and presentation of self-antigens to the T Cell Receptor (TCR) on TH0 cells. […] CD4+ TH0 cells become activated during antigen presentation in the availability of appropriate co-stimulatory signals and undergo maturation into distinct T helper cell populations, based on the cytokine milieu to which they are exposed. TH0 lymphocytes differentiate into T Helper 1 (TH1) cells in the presence of IL-12, whereas they differentiate into T-Helper 2 (TH2) cells in the presence of IL-4.

• #29 Autoimmune Hepatitis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172356-overview

  Autoimmune hepatitis appears to arise a consequence of the breakdown of immune tolerance. Typically, regulatory T cells help to maintain immune homeostasis. A decrease in their number and function may permit unimpeded presentation of liver autoantigen peptides by professional antigen presenting cells (APCs) to CD4+ helper T (Th) cells. This, in turn, may stimulate naive T cells to differentiate into other T-cell lineages (eg, Th1, Th2, Th17). CD4 Th1 cells produce cytokines such as tumor necrosis factor alpha (TNF-) and interferon gamma (IFN-) that stimulate the proliferation of CK8 cytotoxic T lymphocytes (CTLs) and the activation of macrophages. CD4 Th2 cells produce cytokines such as interleukin (IL)-4, IL-5, IL-10, and IL-13 that stimulate B lymphocytes to produce immunoglobulins. Subsequent immunologic reactions ultimately lead to liver cell damage.

• #30 Autoimmmune hepatitis | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-021-00768-8

  The etiology of AIH remains unknown, while pathophysiological mechanisms and risk factors have been described and are constantly updated. […] AIH is characterized histologically by a dense infiltrate of lymphocytes, macrophages and plasma cells in the liver. Despite the presence of circulating autoantibodies and plasma cell liver infiltration, AIH is considered a T cell disease, since B cell activation is a T cell dependent event. The key pathogenic role of T cells in AIH is mirrored by the disease predisposition conferred by HLA class II polymorphisms. […] Loss of tolerance towards self-antigens associated with regulatory T cell (Tregs) dysfunction is central to AIH pathogenesis. Tregs play a central role in maintaining immune tolerance and have been extensively studied in AIH, providing solid evidence of functional and numerical impairment in this condition. In patients with AIH-1 and AIH-2, Tregs are defective in number and this reduction is more evident at diagnosis and during relapses than during drug-induced remission.

• #31 Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018909

  T helper cells that produce IL-17 (Th17 cells) have recently been identified as the third distinct subset of effector T cells. Emerging data suggests that Th17 cells play an important role in the pathogenesis of many liver diseases by regulating innate immunity, adaptive immunity, and autoimmunity. […] The serum levels of IL-17 and IL-23, as well as the frequency of IL-17+ cells in the liver, were significantly elevated in patients with AIH, compared to other chronic hepatitis and healthy controls. […] IL-17 induces IL-6 expression via the MAPK signaling pathway in hepatocytes, which, in turn, may further stimulate Th17 cells and forms a positive feedback loop. […] In conclusion, Th17 cells are key effector T cells that regulate the pathogenesis of AIH, via induction of MAPK dependent hepatic IL-6 expression. Blocking the signaling pathway and interrupting the positive feedback loop are potential therapeutic targets for autoimmune hepatitis.

• #32 Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018909

  T helper cells that produce IL-17 (Th17 cells) have recently been identified as the third distinct subset of effector T cells. Emerging data suggests that Th17 cells play an important role in the pathogenesis of many liver diseases by regulating innate immunity, adaptive immunity, and autoimmunity. […] The serum levels of IL-17 and IL-23, as well as the frequency of IL-17+ cells in the liver, were significantly elevated in patients with AIH, compared to other chronic hepatitis and healthy controls. […] IL-17 induces IL-6 expression via the MAPK signaling pathway in hepatocytes, which, in turn, may further stimulate Th17 cells and forms a positive feedback loop. […] In conclusion, Th17 cells are key effector T cells that regulate the pathogenesis of AIH, via induction of MAPK dependent hepatic IL-6 expression. Blocking the signaling pathway and interrupting the positive feedback loop are potential therapeutic targets for autoimmune hepatitis.

• #33 Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018909

  Autoimmune hepatitis (AIH) is an inflammatory liver condition characterized by interface hepatitis, hypergammaglobulinemia, serum autoantibodies, and satisfactory response to immunosuppressive treatment. Immune reactions against host liver antigens are believed to be a major pathogenic mechanism. […] The recently identified Th17 cells are CD4+ T cells characterized by the secretion of IL-17. […] The cytokine transforming growth factor (TGF-), in the presence of interleukin-6 (IL-6), promotes the differentiation of nave T lymphocytes into Th17 cells, which promote autoimmunity and inflammation. […] The aim of the current study is to investigate whether Th17 cells and/or the IL-17 signaling pathway play a role in the pathogenesis of AIH. […] The degree of hepatic Th17 cell infiltration was positively correlated to the degree of hepatic inflammation and the stage of hepatic fibrosis in AIH patients.

• #34 Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018909

  Autoimmune hepatitis (AIH) is an inflammatory liver condition characterized by interface hepatitis, hypergammaglobulinemia, serum autoantibodies, and satisfactory response to immunosuppressive treatment. Immune reactions against host liver antigens are believed to be a major pathogenic mechanism. […] The recently identified Th17 cells are CD4+ T cells characterized by the secretion of IL-17. […] The cytokine transforming growth factor (TGF-), in the presence of interleukin-6 (IL-6), promotes the differentiation of nave T lymphocytes into Th17 cells, which promote autoimmunity and inflammation. […] The aim of the current study is to investigate whether Th17 cells and/or the IL-17 signaling pathway play a role in the pathogenesis of AIH. […] The degree of hepatic Th17 cell infiltration was positively correlated to the degree of hepatic inflammation and the stage of hepatic fibrosis in AIH patients.

• #35 Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018909

  T helper cells that produce IL-17 (Th17 cells) have recently been identified as the third distinct subset of effector T cells. Emerging data suggests that Th17 cells play an important role in the pathogenesis of many liver diseases by regulating innate immunity, adaptive immunity, and autoimmunity. […] The serum levels of IL-17 and IL-23, as well as the frequency of IL-17+ cells in the liver, were significantly elevated in patients with AIH, compared to other chronic hepatitis and healthy controls. […] IL-17 induces IL-6 expression via the MAPK signaling pathway in hepatocytes, which, in turn, may further stimulate Th17 cells and forms a positive feedback loop. […] In conclusion, Th17 cells are key effector T cells that regulate the pathogenesis of AIH, via induction of MAPK dependent hepatic IL-6 expression. Blocking the signaling pathway and interrupting the positive feedback loop are potential therapeutic targets for autoimmune hepatitis.

• #36 Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018909

  These results indicate that the infiltration of TH17 cells likely contribute to hepatic inflammation and disease progression in AIH. […] IL-6, in conjunction with TGF-, promotes the generation of Th17 cells, while IL-17 can also stimulate IL-6 production. […] We hypothesized that there is a positive-feedback loop between Th17 cells and hepatocytes through IL-6 and IL-17 interaction. […] Our study demonstrated that IL-17 increases the production of IL-6 by hepatocytes, which, in turn, further stimulates Th17 cells and provides a positive feedback loop between Th17 cells and hepatocytes exacerbating the inflammatory process. […] In conclusion, Th17 cells and the IL-17 signaling pathway play a critical role in the pathogenesis of AIH. Restoring the imbalance among Th17 cells and Tregs by interrupting interaction between IL-17 and IL-6 may be an effective therapeutic target for autoimmune liver diseases.

• #37 Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018909

  These results indicate that the infiltration of TH17 cells likely contribute to hepatic inflammation and disease progression in AIH. […] IL-6, in conjunction with TGF-, promotes the generation of Th17 cells, while IL-17 can also stimulate IL-6 production. […] We hypothesized that there is a positive-feedback loop between Th17 cells and hepatocytes through IL-6 and IL-17 interaction. […] Our study demonstrated that IL-17 increases the production of IL-6 by hepatocytes, which, in turn, further stimulates Th17 cells and provides a positive feedback loop between Th17 cells and hepatocytes exacerbating the inflammatory process. […] In conclusion, Th17 cells and the IL-17 signaling pathway play a critical role in the pathogenesis of AIH. Restoring the imbalance among Th17 cells and Tregs by interrupting interaction between IL-17 and IL-6 may be an effective therapeutic target for autoimmune liver diseases.

• #38 Final Diagnosis — Case 554

  https://path.upmc.edu/cases/case554/dx.html

  Over three quarters of AIH cases arise in patients with a well characterized genetic predisposition. In the Caucasian population presence of the HLA-DRB1*0301 and HLA-DRB1*0401 haplotypes confers a significantly increased risk of AIH. Moreover, the DRB1*0301 allele was found to be associated with earlier disease onset and higher frequency of treatment failure. Another allele, HLA-DRB1*1301 could be detected in 45% of North-American AIH patients, who were negative for both DR3 and DR4. On the other hand, patients with an HLA-B8 allele tend to have a more aggressive disease course. In the Italian population HLA-B8-DR3-DQ2, in Japan HLA-DRB1*0405 are the most frequent AIH associated haplotypes. […] The most popular models of AIH pathogenesis are built around the „molecular mimicry” hypothesis. Molecular mimicry describes the phenomena when antibodies directed against foreign antigens cross-react with self-antigens resulting in an autoimmune disorder. The structural similarities found between the epitopes of CYP2D6 and herpes simplex virus as well as between FTCD and herpes virus type 6 indicate that antigen cross-reactions may have a significant role in AIH pathogenesis. Interestingly, anti-LKM antibodies seen in Type 2 AIH are also found in HCV infection, and sometimes anti-LKM-1 positive patients cross-react with the NS3 and NS5a viral proteins. Another intriguing evidence in favor of the „molecular mimicry hypothesis is that immunization of mice with the human CYP2D6 and FTCD alloantigens can be successfully used to generate murine models of AIH.

• #39 Final Diagnosis — Case 554

  https://path.upmc.edu/cases/case554/dx.html

  Over three quarters of AIH cases arise in patients with a well characterized genetic predisposition. In the Caucasian population presence of the HLA-DRB1*0301 and HLA-DRB1*0401 haplotypes confers a significantly increased risk of AIH. Moreover, the DRB1*0301 allele was found to be associated with earlier disease onset and higher frequency of treatment failure. Another allele, HLA-DRB1*1301 could be detected in 45% of North-American AIH patients, who were negative for both DR3 and DR4. On the other hand, patients with an HLA-B8 allele tend to have a more aggressive disease course. In the Italian population HLA-B8-DR3-DQ2, in Japan HLA-DRB1*0405 are the most frequent AIH associated haplotypes. […] The most popular models of AIH pathogenesis are built around the „molecular mimicry” hypothesis. Molecular mimicry describes the phenomena when antibodies directed against foreign antigens cross-react with self-antigens resulting in an autoimmune disorder. The structural similarities found between the epitopes of CYP2D6 and herpes simplex virus as well as between FTCD and herpes virus type 6 indicate that antigen cross-reactions may have a significant role in AIH pathogenesis. Interestingly, anti-LKM antibodies seen in Type 2 AIH are also found in HCV infection, and sometimes anti-LKM-1 positive patients cross-react with the NS3 and NS5a viral proteins. Another intriguing evidence in favor of the „molecular mimicry hypothesis is that immunization of mice with the human CYP2D6 and FTCD alloantigens can be successfully used to generate murine models of AIH.

• #40 Final Diagnosis — Case 554

  https://path.upmc.edu/cases/case554/dx.html

  Over three quarters of AIH cases arise in patients with a well characterized genetic predisposition. In the Caucasian population presence of the HLA-DRB1*0301 and HLA-DRB1*0401 haplotypes confers a significantly increased risk of AIH. Moreover, the DRB1*0301 allele was found to be associated with earlier disease onset and higher frequency of treatment failure. Another allele, HLA-DRB1*1301 could be detected in 45% of North-American AIH patients, who were negative for both DR3 and DR4. On the other hand, patients with an HLA-B8 allele tend to have a more aggressive disease course. In the Italian population HLA-B8-DR3-DQ2, in Japan HLA-DRB1*0405 are the most frequent AIH associated haplotypes. […] The most popular models of AIH pathogenesis are built around the „molecular mimicry” hypothesis. Molecular mimicry describes the phenomena when antibodies directed against foreign antigens cross-react with self-antigens resulting in an autoimmune disorder. The structural similarities found between the epitopes of CYP2D6 and herpes simplex virus as well as between FTCD and herpes virus type 6 indicate that antigen cross-reactions may have a significant role in AIH pathogenesis. Interestingly, anti-LKM antibodies seen in Type 2 AIH are also found in HCV infection, and sometimes anti-LKM-1 positive patients cross-react with the NS3 and NS5a viral proteins. Another intriguing evidence in favor of the „molecular mimicry hypothesis is that immunization of mice with the human CYP2D6 and FTCD alloantigens can be successfully used to generate murine models of AIH.

• #41 Final Diagnosis — Case 554

  https://path.upmc.edu/cases/case554/dx.html

  Over three quarters of AIH cases arise in patients with a well characterized genetic predisposition. In the Caucasian population presence of the HLA-DRB1*0301 and HLA-DRB1*0401 haplotypes confers a significantly increased risk of AIH. Moreover, the DRB1*0301 allele was found to be associated with earlier disease onset and higher frequency of treatment failure. Another allele, HLA-DRB1*1301 could be detected in 45% of North-American AIH patients, who were negative for both DR3 and DR4. On the other hand, patients with an HLA-B8 allele tend to have a more aggressive disease course. In the Italian population HLA-B8-DR3-DQ2, in Japan HLA-DRB1*0405 are the most frequent AIH associated haplotypes. […] The most popular models of AIH pathogenesis are built around the „molecular mimicry” hypothesis. Molecular mimicry describes the phenomena when antibodies directed against foreign antigens cross-react with self-antigens resulting in an autoimmune disorder. The structural similarities found between the epitopes of CYP2D6 and herpes simplex virus as well as between FTCD and herpes virus type 6 indicate that antigen cross-reactions may have a significant role in AIH pathogenesis. Interestingly, anti-LKM antibodies seen in Type 2 AIH are also found in HCV infection, and sometimes anti-LKM-1 positive patients cross-react with the NS3 and NS5a viral proteins. Another intriguing evidence in favor of the „molecular mimicry hypothesis is that immunization of mice with the human CYP2D6 and FTCD alloantigens can be successfully used to generate murine models of AIH.

• #42 Autoimmune hepatitis: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/autoimmune-hepatitis-pathogenesis/print

  Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology characterized by immunologic and autoimmunologic features, generally including the presence of circulating autoantibodies and a high serum globulin concentration. The classification of AIH uses the type of circulating autoantibodies that are present, although there is little evidence to support a role for these antibodies in the pathogenesis of this disorder. The pathogenesis of autoimmune hepatitis will be reviewed here. […] Type 1 autoimmune hepatitis – Type 1 or classic AIH is characterized by circulating antibodies to nuclei (ANA), smooth muscle (ASMA), and IgG F actin (AAA). […] A number of other autoantibodies also occur in this disorder, including atypical perinuclear antineutrophil cytoplasmic antibodies (atypical pANCA), antibodies to the liver-specific asialoglycoprotein receptor, anti SLA/LP (soluble liver antigens/liver-pancreas antigens), and double-stranded DNA. […] Type 2 autoimmune hepatitis – Type 2 AIH is defined by the presence of antibodies to liver/kidney microsomes (ALKM-1) and/or to a liver cytosol antigen (ALC-1), and, rarely, to ALKM-3.

• #43 Autoimmune hepatitis: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/autoimmune-hepatitis-pathogenesis

  Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology characterized by immunologic and autoimmunologic features, generally including the presence of circulating autoantibodies and a high serum globulin concentration. The classification of AIH uses the type of circulating autoantibodies that are present, although there is little evidence to support a role for these antibodies in the pathogenesis of this disorder. […] The pathogenesis of autoimmune hepatitis will be reviewed here.

• #44 Autoimmune hepatitis: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/autoimmune-hepatitis-pathogenesis/print

  Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology characterized by immunologic and autoimmunologic features, generally including the presence of circulating autoantibodies and a high serum globulin concentration. The classification of AIH uses the type of circulating autoantibodies that are present, although there is little evidence to support a role for these antibodies in the pathogenesis of this disorder. The pathogenesis of autoimmune hepatitis will be reviewed here. […] Type 1 autoimmune hepatitis – Type 1 or classic AIH is characterized by circulating antibodies to nuclei (ANA), smooth muscle (ASMA), and IgG F actin (AAA). […] A number of other autoantibodies also occur in this disorder, including atypical perinuclear antineutrophil cytoplasmic antibodies (atypical pANCA), antibodies to the liver-specific asialoglycoprotein receptor, anti SLA/LP (soluble liver antigens/liver-pancreas antigens), and double-stranded DNA. […] Type 2 autoimmune hepatitis – Type 2 AIH is defined by the presence of antibodies to liver/kidney microsomes (ALKM-1) and/or to a liver cytosol antigen (ALC-1), and, rarely, to ALKM-3.

• #45 Autoimmune hepatitis: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/autoimmune-hepatitis-pathogenesis/print

  Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology characterized by immunologic and autoimmunologic features, generally including the presence of circulating autoantibodies and a high serum globulin concentration. The classification of AIH uses the type of circulating autoantibodies that are present, although there is little evidence to support a role for these antibodies in the pathogenesis of this disorder. The pathogenesis of autoimmune hepatitis will be reviewed here. […] Type 1 autoimmune hepatitis – Type 1 or classic AIH is characterized by circulating antibodies to nuclei (ANA), smooth muscle (ASMA), and IgG F actin (AAA). […] A number of other autoantibodies also occur in this disorder, including atypical perinuclear antineutrophil cytoplasmic antibodies (atypical pANCA), antibodies to the liver-specific asialoglycoprotein receptor, anti SLA/LP (soluble liver antigens/liver-pancreas antigens), and double-stranded DNA. […] Type 2 autoimmune hepatitis – Type 2 AIH is defined by the presence of antibodies to liver/kidney microsomes (ALKM-1) and/or to a liver cytosol antigen (ALC-1), and, rarely, to ALKM-3.

• #46 Autoimmune hepatitis: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/autoimmune-hepatitis-pathogenesis/print

  Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology characterized by immunologic and autoimmunologic features, generally including the presence of circulating autoantibodies and a high serum globulin concentration. The classification of AIH uses the type of circulating autoantibodies that are present, although there is little evidence to support a role for these antibodies in the pathogenesis of this disorder. The pathogenesis of autoimmune hepatitis will be reviewed here. […] Type 1 autoimmune hepatitis – Type 1 or classic AIH is characterized by circulating antibodies to nuclei (ANA), smooth muscle (ASMA), and IgG F actin (AAA). […] A number of other autoantibodies also occur in this disorder, including atypical perinuclear antineutrophil cytoplasmic antibodies (atypical pANCA), antibodies to the liver-specific asialoglycoprotein receptor, anti SLA/LP (soluble liver antigens/liver-pancreas antigens), and double-stranded DNA. […] Type 2 autoimmune hepatitis – Type 2 AIH is defined by the presence of antibodies to liver/kidney microsomes (ALKM-1) and/or to a liver cytosol antigen (ALC-1), and, rarely, to ALKM-3.

• #47 Autoimmmune hepatitis | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-021-00768-8

  Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.

• #48 Autoimmmune hepatitis | Cellular & Molecular Immunology

  https://www.nature.com/articles/s41423-021-00768-8

  The involvement of Th 17, which secrete the proinflammatory cytokines IL-17, IL-22 and TNF and promote IL-6 secretion by hepatocytes, has been investigated more recently. […] Emerging data suggest that follicular T helper (TFH) cells, also known as follicular B helper T cells, are involved in the pathogenesis of AIH. […] The immune response in AIH is believed to be initiated by the presentation of self-antigenic peptides, as yet unknown, to the T cell receptor (TCR) of uncommitted naive CD4 T-helper (Th0) lymphocytes. Self-antigens of interest are CYP2D6 and FTCD in AIH-2 and human SepSecS-tRNASec complex (SEPSECS) in AIH-1, as the formers are the targets of anti-LKM1 and anti-LC1, while the latter is the target of anti-soluble liver antigen (anti-SLA).

• #49 Autoimmune Hepatitis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172356-overview

  Evidence for an autoimmune pathogenesis includes the following: Hepatic histopathologic lesions composed predominantly of cytotoxic T cells and plasma cells; Circulating autoantibodies (ie, nuclear, smooth muscle, thyroid, liver-kidney microsomal, soluble liver antigen, hepatic lectin); Association with hypergammaglobulinemia and the presence of a rheumatoid factor (RF); Association with other autoimmune diseases; Response to steroid and/or immunosuppressive therapy.

• #50 Final Diagnosis — Case 554

  https://path.upmc.edu/cases/case554/dx.html

  Activated self-reactive lymphocytes are more likely to be trapped in liver sinusoids than in other organs, as liver sinusoidal cells express various cell adhesion molecules including ICAM-1 and VCAM-1 capable binding to leukocytes surface proteins. The liver infiltrating lymphocyte population in AIH is predominantly composed of CD4+ Th1 cells, suggesting that self-antigen recognizing T-cells could contribute to AIH pathogenesis. Autoreactive CD8+ T-cells are also found in AIH. They are able to recognize antigens on the hepatocyte surface, and may trigger apoptosis through activation of the TNF- , Fas/FasL pathways. Finally, the immune mediated destruction of hepatocytes, either through soluble or cellular factors, may lead to unmasking of further intracellular autoantigens resulting in a self-enhancing cycle of events.

• #51

  https://journals.lww.com/ajg/fulltext/2001/04000/understanding_the_pathogenesis_of_autoimmune.54.aspx

  The aim of this study was to review the pathogenic mechanisms of autoimmune hepatitis, identify gaps in knowledge, and focus future investigative efforts. […] Autoimmune hepatitis is a consequence of autoantigen exposure, genetic predisposition, and defective immunoregulatory mechanisms. Autoantigen is optimally presented by class II molecules of the major histocompatibility complex that have lysine residues at position DR71 of the antigen-binding groove. Cytokines and nondisease-specific autoimmune promoters modulate immune reactivity. Cell-mediated and antibody-dependent mechanisms contribute to hepatocyte injury. […] Multiple disturbances in the homeostatic mechanisms that preserve self-tolerance are likely in autoimmune hepatitis. Future investigations must focus on individual determinants of autoantigen presentation, immunocyte activation, and liver cell destruction. Findings can then be integrated into a comprehensive knowledge base that may be applicable to other autoimmune diseases.

• #52

  https://xiahepublishing.com/2310-8819/JCTH-2013-00015

  In health, immunotolerance to liver autoantigens is maintained by effective control of CD4+CD25+FOXP3+Tregs over CD4+ and CD8+ autoreactive T lymphocytes. […] The machinery enabling Tregs to modulate effector immune responses relies on the expression of CD39, an ectonucleotidase ultimately leading to the generation of immunomodulatory adenosine. […] In AIH, Tregs are numerically defective and express low levels of CD39. This results in poor generation of adenosine and ineffective control over autoreactive lymphocytes, with consequent perpetuation of hepatocyte damage. […] Treatment-induced remission of AIH is associated with restoration of Treg function. […] Natural killer T (NKT) cells may also be involved in the pathogenesis of AIH. […] The purinergic receptor P2X7 recognizes extracellular ATP, and is crucial in regulating the function of NKT cells.

• #53 The progress of autoimmune hepatitis research and future challenges

  https://www.degruyter.com/document/doi/10.1515/med-2023-0823/html?lang=en

  The liver is constantly exposed to various antigens due to its location and function, indicating the tolerance or responsiveness of the hepatic immune system. Cytokines of immunosuppressive cells provide tolerance in the liver, migrating with immune mediators through the hepatic sinusoids to the liver parenchyma. Under normal circumstances, the livers tolerance can result from the joint action of immune cells, parenchymal cells, epithelial and endothelial cells, and the microenvironment. The concentration of the immunosuppressive cytokine IL-10 is normally high in the liver. Besides, most liver antigen-presenting cells, including DC cells and liver sinusoidal endothelial cells, have low levels of MHC class II and co-stimulatory molecules CD80/CD86, thereby inducing an immune tolerance phenotype. In addition, the proliferation of Foxp3+ Tregs in the liver mediated by the Notch signaling pathway can also release IL-10 and enhance the immunosuppressive environment. Moreover, CD8+ T cells generated in lymph nodes have a strong intrahepatic antigen-specific immune response, while CD8+ T cells activated in the tolerogenic environment of the liver are more defective in inducing cytotoxic immune responses and have a short half-life. During autoimmune diseases such as AIH, liver tolerance often collapses. Recent studies have revealed that the administration of anti-CD20 antibodies has the potential to considerably diminish the expression of MHC class II and CD80 molecules on B cells. Consequently, this intervention can decrease the capacity of B cells to deliver self-antigens to T cells, resulting in a reduction in T cell activation and proliferation. Additionally, this intervention alleviates inflammation in the liver and mitigates the breakdown of hepatocytes. Chronic hepatitis is mainly caused by the interaction of multiple immune cells, such as lymphocytes, macrophages, natural killer T cells (NKT), etc. These cells secrete TNF, interferon-gamma (IFN-), and other pro-inflammatory cytokines. The liver inflammatory process could be initiated by presenting autoantigenic peptides to helper T-cell receptors, leading to Th1, Th2, and Th17 cell recruitment into the tissue. These effector cells begin an immune response cascade depending on the release of cytokines. The regulatory T cells (Tregs) recruitment process involves lymphocytes interacting with surface molecules present in endothelial cells. In the liver, Treg secretes the immunosuppressive cytokines IL-10 and transforming growth factor beta to inhibit the effector cell proliferation and action. T cells are innate lymphocytes recognizing non-peptide antigens and stress-induced ligands into two distinct subpopulations, including IFN- or IL-17-induced T cell production. Moreover, IL-17A, synthesized by T cells, controlled hepatocyte injury in J18 knockout mice, an AIH model. T cells can also secrete IL-17 and cause damage to the liver. Intraepithelial lymphocytes are directly responsible for the cytolysis of effector cells and antigen-presenting cells through the granzyme-perforin, Fas-Fas ligand, and lymphotoxin pathways. They are a key population in the regulation of immune responses in tissues. Both relative and absolute counts of T cells were elevated in the peripheral blood of patients with AIH, which is characteristic of patients with AIH. Selective enrichment of the V1 subpopulation of T cells has also been found in Takayasu arteritis and systemic sclerosis, indicating that T cells are involved in the pathogenesis of autoimmunity. In addition, in another study, it was confirmed that the number of T cells increased significantly during the active phase of AIH, and the production of its effector molecule granzyme B also increased significantly, which was consistent with the levels of liver damage markers alanine aminotransferase (ALT) and bilirubin. Consistent with the increase, the proportion of the V1 subpopulation and the ability of this cell population to produce IFN- increased. This process can promote B cells to stimulate plasma cells to release autoantibodies, causing damage to liver cells. In other autoimmune diseases, imbalances in the physiological levels of T cells are also associated with inflammatory processes. A recent study found that AIH models could also be generated by transferring T cells from TOX-deficient mice into new mice. It is well known that invariant natural killer T (iNKT) cells (also called type I NKT cells) express and characterize a semi-invariant T cell receptor (TCR). The TCR region of all iNKT cells contains the canonical V14-J18 TCR chain. Thus, J18 knockout can hinder the synthesis of TCR and lead to the lack of NKT cells. In addition, the TCR of human and mouse NKT cells contains V14J18 chain and V24J18 chain, respectively. Therefore, J18 knockout mice have extremely important reference significance for the study of human J18. The current consensus among immune cells in AIH is that this autoimmune disease is caused by the signal presentation of self-antigens to uncommitted T helper (Th0) through HLA II molecules on antigen-presenting cells. At this time, Th0 cells are activated and differentiate into Th1, Th2, and Th17 cells according to different cytokines. When the cytokine environment is rich in IL-12, Th0 cells differentiate into Th1 cells. When the cytokine environment is rich in IL-4, Th0 cells differentiate into Th2 cells, while in the presence of IL-1, IL-6, and TGF-, Th0 cells differentiate into Th17 cells. When differentiated into Th1 cells, these cells can secrete IL-2 and IFN-. The former cytokine can activate macrophages to secrete IL-1 and TNF-, thereby damaging liver cells. The latter stimulates cytotoxic lymphocytes and enhances the expression of HLA class I molecules on APCs and HLA class II molecules on hepatocytes. When differentiated into Th2 cells, IL-4, IL-10, and IL-13 can be produced, which can induce B cells to mature into plasma cells and then produce autoantibodies. Finally, when the environment is rich in IL-6 and TGF-, these cytokines will inhibit the function of Treg cells and induce the differentiation of Th0 cells into Th2 cells. In addition, NKT cells have been shown to be significantly reduced in AIH patients, which leads to reduced secretion of IL-4, an inhibitor of Th17 development. Th17 will secrete IL-17, IL-22, and TNF, causing damage to liver cells and inducing hepatocytes to secrete IL-6. The secreted IL-6 will further stimulate Th17 cells to produce corresponding cytokines. During this process, T cells can also secrete IL-17 to play a similar role. Humoral immunity is also associated with liver injury in AIH. As we know, anti-nuclear autoantibodies (ANA) and/or anti-smooth muscle autoantibodies (SMA) are positive in AIH-1, while anti-liver-kidney microsomal and/or anti-hepatic cytoplasmic antibodies are present in AIH-2. The autoantigens targeted by AIH-2 autoantibodies are anti-liver and kidney microsomal antibody type 1 (LKM1) cytochrome P450 2D6, CYP2D6, and anti-lc1 formyl aminotransferase-ring deaminase. Stimulation of CYP2D6 favors Th1 responses as its peptide aa 305324 can induce high levels of interferon production. In models of AIH caused by CYP2D6 plasmids, there was a persistent elevation in transaminases, chronic inflammation, and liver fibrosis. These changes were accompanied by increased Th1 responses and decreased liver-infiltrating Treg cells. In addition, CYP2D6 can be inhibited by LKM1-positive serum in vitro, leading to hepatocyte damage, which was mentioned in the manuscript. LKM1 could be a diagnostic marker for AIH type 2. Cytochrome P4502D6 (CYP2D6) protein can be found on the surface of human liver cells. This cytochrome can be inhibited by LKM1-positive serum in vitro, leading to hepatocyte damage.

• #54 Pathogenesis of autoimmune hepatitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8422914/

  Autoimmune hepatitis (AIH) is a chronic progressive liver disease whose etiology and pathogenesis are not yet clear. It is currently believed that the occurrence of AIH is closely related to genetic susceptibility and immune abnormalities, and other factors such as environment, viral infection and drugs that may cause immune dysfunction. […] Although the exact pathogenesis of AIH is still unclear, there are many theories, and the continuous in-depth research on its pathogenesis has led to development in treatment of AIH. […] The pathogenesis of AIH still needs further research.

• #55 Autoimmune Hepatitis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172356-overview

  Autoimmune hepatitis is a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis. Progressive fibrosis may lead to cirrhosis. […] The proposed pathogenesis of autoimmune hepatitis involves the combination of genetic predisposition and environmental triggers. The genetic predisposition may relate to several defects in immunologic control of autoreactivity. An environmental agent may trigger the autoimmune response against liver antigens, causing necroinflammatory liver damage, fibrosis, and, eventually, cirrhosis, if left untreated. […] Genetic susceptibility to developing autoimmune hepatitis has been associated with the human leukocyte antigen (HLA) haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients.

• #56 Pathogenesis of Autoimmune Hepatitis—Cellular and Molecular Mechanisms

  https://www.mdpi.com/1422-0067/22/24/13578

  Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. Epigenetic pathways intervene in various physiological mechanisms, such as cell division and differentiation and cell development and growth, and play an important role in various phenotypic features in health and disease. The epigenome is prone to changes and can be modified by variable environmental factors, including infection, diet, medication, and chemicals. […] Some of these factors are incompletely confirmed, such as CTLA4, FAS/FASL, AIRE, and GATA2 mutations, but the predisposing HLA-D allele, SH2B3 risk allele, female gender, age, hormonal status, and exposure to viral and drug triggers have been demonstrated to be associated with the risk of developing autoimmune hepatitis.

• #57 Pathogenesis of Autoimmune Hepatitis—Cellular and Molecular Mechanisms

  https://www.mdpi.com/1422-0067/22/24/13578?type=check_update&version=1

  Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. […] Some of these factors are incompletely confirmed, such as CTLA4, FAS/FASL, AIRE, and GATA2 mutations, but the predisposing HLA-D allele, SH2B3 risk allele, female gender, age, hormonal status, and exposure to viral and drug triggers have been demonstrated to be associated with the risk of developing autoimmune hepatitis.

• #58 Pathogenesis of Autoimmune Hepatitis—Cellular and Molecular Mechanisms

  https://www.mdpi.com/1422-0067/22/24/13578

  Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. Epigenetic pathways intervene in various physiological mechanisms, such as cell division and differentiation and cell development and growth, and play an important role in various phenotypic features in health and disease. The epigenome is prone to changes and can be modified by variable environmental factors, including infection, diet, medication, and chemicals. […] Some of these factors are incompletely confirmed, such as CTLA4, FAS/FASL, AIRE, and GATA2 mutations, but the predisposing HLA-D allele, SH2B3 risk allele, female gender, age, hormonal status, and exposure to viral and drug triggers have been demonstrated to be associated with the risk of developing autoimmune hepatitis.

• #59 Pathogenesis of Autoimmune Hepatitis—Cellular and Molecular Mechanisms

  https://www.mdpi.com/1422-0067/22/24/13578

  Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. Epigenetic pathways intervene in various physiological mechanisms, such as cell division and differentiation and cell development and growth, and play an important role in various phenotypic features in health and disease. The epigenome is prone to changes and can be modified by variable environmental factors, including infection, diet, medication, and chemicals. […] Some of these factors are incompletely confirmed, such as CTLA4, FAS/FASL, AIRE, and GATA2 mutations, but the predisposing HLA-D allele, SH2B3 risk allele, female gender, age, hormonal status, and exposure to viral and drug triggers have been demonstrated to be associated with the risk of developing autoimmune hepatitis.

• #60 Pathogenesis of Autoimmune Hepatitis—Cellular and Molecular Mechanisms

  https://www.mdpi.com/1422-0067/22/24/13578

  Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. Epigenetic pathways intervene in various physiological mechanisms, such as cell division and differentiation and cell development and growth, and play an important role in various phenotypic features in health and disease. The epigenome is prone to changes and can be modified by variable environmental factors, including infection, diet, medication, and chemicals. […] Some of these factors are incompletely confirmed, such as CTLA4, FAS/FASL, AIRE, and GATA2 mutations, but the predisposing HLA-D allele, SH2B3 risk allele, female gender, age, hormonal status, and exposure to viral and drug triggers have been demonstrated to be associated with the risk of developing autoimmune hepatitis.

• #61 Recent advances in the diagnosis and management of autoimmune hepatitis – Polish Archives of Internal Medicine

  https://www.mp.pl/paim/issue/article/16334/

  We recently found DNA methylation changes in circulating immune cells and at the histological level in patients with AIH, which were associated with disease activity and influenced by immunosuppressive treatment. […] The clinical presentation of AIH in adults is highly heterogeneous. […] Detection of autoantibodies is essential not only for the diagnosis but also for the classification of AIH. […] The presence of soluble liver antigens / liver pancreas antibodies (anti-SLA/LP) was formerly considered a third category of AIH. […] Every patient with suspected AIH should have a liver biopsy performed unless there is a contraindication. […] The International AIH Pathology Group recently issued a consensus statement that proposed a uniform approach to the diagnosis of AIH at the histological level.

• #62 The progress of autoimmune hepatitis research and future challenges

  https://www.degruyter.com/document/doi/10.1515/med-2023-0823/html?lang=en

  AIH causes autoimmune intolerance, resulting in autoimmune cells attacking hepatocytes. However, AIH pathogenesis, which could involve genetic predisposition, environmental factors, and immune system dysregulation, remains incompletely elucidated. […] AIH is a polygenic disease of unknown etiology, and genetic factors can influence the disease progression and clinical phenotype of AIH. AIH patients are associated with extrahepatic autoimmune disease, and about 40% have an autoimmune disease history in the family. Genome-wide association studies have revealed that the human leukocyte antigen (HLA) locus and some non-HLA loci are primarily associated with the AIH region. AIH genetic susceptibility is related to HLA region genes on the short arm of chromosome 6, particularly with DRB1 allelic variants. The diagnostic effectiveness of HLA susceptibility alleles in identifying individuals with AIH is widely recognized, leading to their inclusion in the AIH diagnostic criteria. MHC class II HLA DRB1 alleles DRB1*0301 and DRB1*0401 encode amino acid sequences that render humans in Europe and North America more susceptible to AIH-1. DRB1*15:01 can reduce the risk of AIH1 in the population. Besides, DRB1*03, DRB1*07, and DQB1*02:01 will make the population more susceptible to AIH-2. Other genes also affect AIH development since some patients with the disease do not carry HLA alleles. In addition to non-HLA genes having immunological significance, the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene + 49A/G genotype was significantly correlated with AIH susceptibility. The CTLA-4 gene, located on chromosome 2q33, includes a single base exchange polymorphism in exon 1, in which there is a guanine replaced by adenine at position 49, resulting in the expressed protein There is a threonine instead of alanine. A recent investigation obtained the genotypes of 155 persons diagnosed with AIH who belong to the Nordic Caucasian population and 102 healthy individuals from the same racial background. The expression of each genotype was AA = 50/155 patients vs 51/102 controls; AG = 84/155 patients vs 38/102 controls; GG = 21/155 patients vs 13/102 controls, x2 = 8.94, P = 0.011). In addition, there is a synergistic effect between CTLA-4 + 49A/G and DRB1*03:01 on AIH-1 susceptibility. A recent study showed that the GG genotype of CTLA-4 CT 60 accounted for 36.2% of AIH patients, significantly higher than that of the control group (10.0%). The strength of the correlation between the two variables, as measured by Cramers V, was determined to be 0.341, indicating a moderate level of correlation. The bias-corrected Cramers V demonstrated a moderate correlation, exhibiting a correlation coefficient of 0.322. The CTLA-4 GG genotype significantly increases the risk of AIH-1 when patients have HLA DRB1*0301 in their genotype. In Tunisian patients, the CTLA-4 + 49 position GG genotype was also positively associated with AIH susceptibility. In addition, tumor necrosis factor–inducible protein 3 (TNFAIP3) is a genetically encoded ubiquitinating enzyme whose rs10499194 T allele and CT genotype are associated with an elevated risk of developing AIH. Thus, the rs10499194 polymorphism is an AIH locus for candidate susceptibility. Patients in the Japanese population who had detrimental mutations in TNFAIP3 had an increased risk of cirrhosis-related AIH. The receptor for Fas was found to be significantly elevated in lymphocytes from AIH patients. Furthermore, the surface expression of Fas in CD4+ and CD8+ T lymphocyte subsets was significantly higher in AIH patients compared with normal subjects. Expanded Fas+ T cells also reflect the presence of persistent antigen-specific or non-specific activation in the body and abnormalities in the peripheral loss of activated lymphocytes. A Japanese study observed that Fas polymorphisms and AIH development were strongly correlated with genetic factors. And the Fas-670A allele carriers showed an elevated risk of developing AIH. Inflammatory cytokines are also involved in AIH development. For instance, the IL-4-590 C/T polymorphism and the IL-4-33 TT genotype increase AIH susceptibility. In vivo intervention with recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) can reduce the secretion of TNF-alpha and interleukin-17 (IL-17) and the infiltration of inflammatory cells in the liver thereby inhibiting ConA-induced hepatitis. CCN1 promotes inflammation by upregulating IL-6 production in ConA mice through the 61/PI3K/Akt/NF-B pathway. Recently, miRNAs have also demonstrated a crucial impact on AIH development. A study comparing serum miRNAs showed significant differences between healthy individuals and AIH patients. Compared with controls, serum levels of miR-29a were decreased, miR-378, let-7b, miR-122 and miR-192 were increased, and miR-574-3p, miR-193a-5p and miR-148a were unchanged. This indicates that the combination can be utilized to differentiate between people with AIH. Furthermore, a substantial correlation was found between miR-557 and a higher chance of recurrence. Additionally, it might also distinguish AIH patients from hepatitis C (HCV) patients, primary biliary hepatitis patients with cholangitis, and non-alcoholic steatohepatitis patients. The expression level of miR-155 was significantly elevated in liver specimens of AIH patients but was reduced in peripheral blood mononuclear cells. In the CoA model, the level of miR-223 in Kupffer cells of mice with early liver damage was significantly increased, and transfection of miR-223 mimics could inhibit the activation of Kupffer cells after Con A stimulation.

• #63 A Concise Review of Autoimmune Liver Diseases | IntechOpen

  https://www.intechopen.com/chapters/48381

  Regulatory T cells (Treg) play an essential role in the homeostasis and prevention of autoimmune conditions. […] In AIH, the number of Tregs is normal but their function is impaired. […] Type 1 AIH is associated with human leukocyte antigen (HLA) DR3 (HLA-DRB1*0301) and DR4 (HLA-DRB1*0401) in white North Europe and North American patients. […] Proposed pathway of pathogenesis in AIH has been shown in Figure 1. […] Autoimmune hepatitis (AIH) is initiated by the presence of auto antigen peptide onto antigen presenting cells (APC) which activates T helper cells (Th0) due to interleukins (IL) 2 and 4. Upon activation of Th0, it can differentiate into Th1 and Th2 cellular pathway. Th1 produces IL2 and Interferon-gamma (IFN-r) which subsequently activates CD8 lymphocytes.

• #64 The Pathogenesis of Autoimmune Hepatitis | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-60761-569-9_2

  The pathogenesis of AIH, a progressive necroinflammatory disease of the liver, is incompletely understood. Studies in human beings and animal models indicate that it exhibits features shared with classical autoimmune, as well as, non-autoimmune-mediated inflammatory diseases. Despite an incomplete understanding, it is now clear that the pathogenesis of AIH involves genetic factors, both immune and nonimmune; environmental triggering events; the interplay between innate and adaptive immunity, especially in the unique immunological microenvironment of the liver; a permissive immune response repertoire capable of reacting to hepatic autoantigens or their molecular mimics; and failure of immunoregulatory mechanisms to control or terminate the autoimmune response causing hepatic necroinflammation and progressive fibrosis. […] Knowledge of the pathogenesis of AIH can aid the clinician in the use of immunosuppressive medications to retard or prevent disease progression, and will likely lead to novel therapies in the near future.

• #65 Autoimmune hepatitis – Wikipedia

  https://en.wikipedia.org/wiki/Autoimmune_hepatitis

  Autoimmune hepatitis, formerly known as lupoid hepatitis, plasma cell hepatitis, or autoimmune chronic active hepatitis, is a chronic, autoimmune disease of the liver that occurs when the body’s immune system attacks liver cells, causing the liver to be inflamed. […] Anomalous presentation of MHC class II receptors on the surface of liver cells, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated immune response against the body’s own liver, resulting in autoimmune hepatitis. This abnormal immune response results in inflammation of the liver, which can lead to further symptoms and complications such as fatigue and cirrhosis. […] The prevailing theory for the development of autoimmune hepatitis is thought to be the interplay of genetic predisposition, an environmental trigger (virus, drugs, herbs, immunizations), and failure of the native immune system resulting in chronic inflammation of hepatocytes and subsequent fibrosis of the liver.

• #66 Immunopathogenesis of Autoimmune Hepatitis | Immunopaedia

  https://www.immunopaedia.org.za/breaking-news/immunopathogenesis-of-autoimmune-hepatitis/

  Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that occurs at any age and mainly affects women. The pathogenesis of AIH is complex and was long unknown. Understanding the immunopathogenesis of AIH is crucial for the treatment of AIH patients and the development of novel AIH therapeutic strategies. […] Despite these effective mechanisms, loss of tolerance in AIH can occur through a combination of genetic predisposition, environmental stimulus and an imbalance in immunological regulatory mechanisms. […] A dynamic balance between proinflammatory Th17 and immunosuppressive Tregs can critically determine the immunopathology of AIH. […] There is a lack of innovative therapies to treat AIH, therefore understanding pathogenic mechanisms is a must, especially the role of Tregs and auto-reactive B cells. Recent case reports have highlighted the potential role of B cell depletion therapy (antiCD20) in refractory cases of AIH. Inhibition of BAFF receptor is a novel therapeutic approach.

• #67 Autoimmune hepatitis: Risk factors, pathophysiology, diagnosis an

  https://www.openaccessjournals.com/articles/autoimmune-hepatitis-risk-factors-pathophysiology-diagnosis-and-management-15645.html

  Autoimmune hepatitis is characterized as an entity of chronic hepatitis that must be distinguished from chronic viral hepatitis, drug-induced and alcohol-induced hepatitis and idiopathic chronic hepatitis. The pathogenesis of autoimmune hepatitis is very complex and includes interactions between the tolerant liver, environmental triggers, and dysregulated immunological mechanisms. […] The pathogenesis of AIH is very complex and includes interactions between the tolerant liver, environmental triggers, and dysregulated immunological mechanisms. […] The immune response in autoimmune hepatitis is likely induced by the presentation of self-antigens to uncommitted naive CD4+ T Helper cells (TH0). T cells targeting the self-epitope become primed and expand, which leads to induction and perpetuation of autoimmune-mediated liver damage. Molecular mimicry is well explained in AIH-2, in which the key target of humoral and cellular autoimmune responses has been defined as the liver enzyme Cytochrome P450 2D6 (CYP2D6), which is the target of the anti- LKM1 antibody. An amino acid sequence of CYP2D6 reveals an elevated level of homology with proteins encoded by HCV and members of the herpes virus family (for example, cytomegalovirus, EpsteinBarr virus, and herpes simplex virus).

• #68 Autoimmune Hepatitis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172356-overview

  Autoimmune hepatitis appears to arise a consequence of the breakdown of immune tolerance. Typically, regulatory T cells help to maintain immune homeostasis. A decrease in their number and function may permit unimpeded presentation of liver autoantigen peptides by professional antigen presenting cells (APCs) to CD4+ helper T (Th) cells. This, in turn, may stimulate naive T cells to differentiate into other T-cell lineages (eg, Th1, Th2, Th17). CD4 Th1 cells produce cytokines such as tumor necrosis factor alpha (TNF-) and interferon gamma (IFN-) that stimulate the proliferation of CK8 cytotoxic T lymphocytes (CTLs) and the activation of macrophages. CD4 Th2 cells produce cytokines such as interleukin (IL)-4, IL-5, IL-10, and IL-13 that stimulate B lymphocytes to produce immunoglobulins. Subsequent immunologic reactions ultimately lead to liver cell damage.

• #69 The progress of autoimmune hepatitis research and future challenges

  https://www.degruyter.com/document/doi/10.1515/med-2023-0823/html?lang=en

  The liver is constantly exposed to various antigens due to its location and function, indicating the tolerance or responsiveness of the hepatic immune system. Cytokines of immunosuppressive cells provide tolerance in the liver, migrating with immune mediators through the hepatic sinusoids to the liver parenchyma. Under normal circumstances, the livers tolerance can result from the joint action of immune cells, parenchymal cells, epithelial and endothelial cells, and the microenvironment. The concentration of the immunosuppressive cytokine IL-10 is normally high in the liver. Besides, most liver antigen-presenting cells, including DC cells and liver sinusoidal endothelial cells, have low levels of MHC class II and co-stimulatory molecules CD80/CD86, thereby inducing an immune tolerance phenotype. In addition, the proliferation of Foxp3+ Tregs in the liver mediated by the Notch signaling pathway can also release IL-10 and enhance the immunosuppressive environment. Moreover, CD8+ T cells generated in lymph nodes have a strong intrahepatic antigen-specific immune response, while CD8+ T cells activated in the tolerogenic environment of the liver are more defective in inducing cytotoxic immune responses and have a short half-life. During autoimmune diseases such as AIH, liver tolerance often collapses. Recent studies have revealed that the administration of anti-CD20 antibodies has the potential to considerably diminish the expression of MHC class II and CD80 molecules on B cells. Consequently, this intervention can decrease the capacity of B cells to deliver self-antigens to T cells, resulting in a reduction in T cell activation and proliferation. Additionally, this intervention alleviates inflammation in the liver and mitigates the breakdown of hepatocytes. Chronic hepatitis is mainly caused by the interaction of multiple immune cells, such as lymphocytes, macrophages, natural killer T cells (NKT), etc. These cells secrete TNF, interferon-gamma (IFN-), and other pro-inflammatory cytokines. The liver inflammatory process could be initiated by presenting autoantigenic peptides to helper T-cell receptors, leading to Th1, Th2, and Th17 cell recruitment into the tissue. These effector cells begin an immune response cascade depending on the release of cytokines. The regulatory T cells (Tregs) recruitment process involves lymphocytes interacting with surface molecules present in endothelial cells. In the liver, Treg secretes the immunosuppressive cytokines IL-10 and transforming growth factor beta to inhibit the effector cell proliferation and action. T cells are innate lymphocytes recognizing non-peptide antigens and stress-induced ligands into two distinct subpopulations, including IFN- or IL-17-induced T cell production. Moreover, IL-17A, synthesized by T cells, controlled hepatocyte injury in J18 knockout mice, an AIH model. T cells can also secrete IL-17 and cause damage to the liver. Intraepithelial lymphocytes are directly responsible for the cytolysis of effector cells and antigen-presenting cells through the granzyme-perforin, Fas-Fas ligand, and lymphotoxin pathways. They are a key population in the regulation of immune responses in tissues. Both relative and absolute counts of T cells were elevated in the peripheral blood of patients with AIH, which is characteristic of patients with AIH. Selective enrichment of the V1 subpopulation of T cells has also been found in Takayasu arteritis and systemic sclerosis, indicating that T cells are involved in the pathogenesis of autoimmunity. In addition, in another study, it was confirmed that the number of T cells increased significantly during the active phase of AIH, and the production of its effector molecule granzyme B also increased significantly, which was consistent with the levels of liver damage markers alanine aminotransferase (ALT) and bilirubin. Consistent with the increase, the proportion of the V1 subpopulation and the ability of this cell population to produce IFN- increased. This process can promote B cells to stimulate plasma cells to release autoantibodies, causing damage to liver cells. In other autoimmune diseases, imbalances in the physiological levels of T cells are also associated with inflammatory processes. A recent study found that AIH models could also be generated by transferring T cells from TOX-deficient mice into new mice. It is well known that invariant natural killer T (iNKT) cells (also called type I NKT cells) express and characterize a semi-invariant T cell receptor (TCR). The TCR region of all iNKT cells contains the canonical V14-J18 TCR chain. Thus, J18 knockout can hinder the synthesis of TCR and lead to the lack of NKT cells. In addition, the TCR of human and mouse NKT cells contains V14J18 chain and V24J18 chain, respectively. Therefore, J18 knockout mice have extremely important reference significance for the study of human J18. The current consensus among immune cells in AIH is that this autoimmune disease is caused by the signal presentation of self-antigens to uncommitted T helper (Th0) through HLA II molecules on antigen-presenting cells. At this time, Th0 cells are activated and differentiate into Th1, Th2, and Th17 cells according to different cytokines. When the cytokine environment is rich in IL-12, Th0 cells differentiate into Th1 cells. When the cytokine environment is rich in IL-4, Th0 cells differentiate into Th2 cells, while in the presence of IL-1, IL-6, and TGF-, Th0 cells differentiate into Th17 cells. When differentiated into Th1 cells, these cells can secrete IL-2 and IFN-. The former cytokine can activate macrophages to secrete IL-1 and TNF-, thereby damaging liver cells. The latter stimulates cytotoxic lymphocytes and enhances the expression of HLA class I molecules on APCs and HLA class II molecules on hepatocytes. When differentiated into Th2 cells, IL-4, IL-10, and IL-13 can be produced, which can induce B cells to mature into plasma cells and then produce autoantibodies. Finally, when the environment is rich in IL-6 and TGF-, these cytokines will inhibit the function of Treg cells and induce the differentiation of Th0 cells into Th2 cells. In addition, NKT cells have been shown to be significantly reduced in AIH patients, which leads to reduced secretion of IL-4, an inhibitor of Th17 development. Th17 will secrete IL-17, IL-22, and TNF, causing damage to liver cells and inducing hepatocytes to secrete IL-6. The secreted IL-6 will further stimulate Th17 cells to produce corresponding cytokines. During this process, T cells can also secrete IL-17 to play a similar role. Humoral immunity is also associated with liver injury in AIH. As we know, anti-nuclear autoantibodies (ANA) and/or anti-smooth muscle autoantibodies (SMA) are positive in AIH-1, while anti-liver-kidney microsomal and/or anti-hepatic cytoplasmic antibodies are present in AIH-2. The autoantigens targeted by AIH-2 autoantibodies are anti-liver and kidney microsomal antibody type 1 (LKM1) cytochrome P450 2D6, CYP2D6, and anti-lc1 formyl aminotransferase-ring deaminase. Stimulation of CYP2D6 favors Th1 responses as its peptide aa 305324 can induce high levels of interferon production. In models of AIH caused by CYP2D6 plasmids, there was a persistent elevation in transaminases, chronic inflammation, and liver fibrosis. These changes were accompanied by increased Th1 responses and decreased liver-infiltrating Treg cells. In addition, CYP2D6 can be inhibited by LKM1-positive serum in vitro, leading to hepatocyte damage, which was mentioned in the manuscript. LKM1 could be a diagnostic marker for AIH type 2. Cytochrome P4502D6 (CYP2D6) protein can be found on the surface of human liver cells. This cytochrome can be inhibited by LKM1-positive serum in vitro, leading to hepatocyte damage.

• #70

  https://journals.lww.com/ajg/fulltext/2001/04000/understanding_the_pathogenesis_of_autoimmune.54.aspx

  The aim of this study was to review the pathogenic mechanisms of autoimmune hepatitis, identify gaps in knowledge, and focus future investigative efforts. […] Autoimmune hepatitis is a consequence of autoantigen exposure, genetic predisposition, and defective immunoregulatory mechanisms. Autoantigen is optimally presented by class II molecules of the major histocompatibility complex that have lysine residues at position DR71 of the antigen-binding groove. Cytokines and nondisease-specific autoimmune promoters modulate immune reactivity. Cell-mediated and antibody-dependent mechanisms contribute to hepatocyte injury. […] Multiple disturbances in the homeostatic mechanisms that preserve self-tolerance are likely in autoimmune hepatitis. Future investigations must focus on individual determinants of autoantigen presentation, immunocyte activation, and liver cell destruction. Findings can then be integrated into a comprehensive knowledge base that may be applicable to other autoimmune diseases.

• #71 Final Diagnosis — Case 554

  https://path.upmc.edu/cases/case554/dx.html

  Activated self-reactive lymphocytes are more likely to be trapped in liver sinusoids than in other organs, as liver sinusoidal cells express various cell adhesion molecules including ICAM-1 and VCAM-1 capable binding to leukocytes surface proteins. The liver infiltrating lymphocyte population in AIH is predominantly composed of CD4+ Th1 cells, suggesting that self-antigen recognizing T-cells could contribute to AIH pathogenesis. Autoreactive CD8+ T-cells are also found in AIH. They are able to recognize antigens on the hepatocyte surface, and may trigger apoptosis through activation of the TNF- , Fas/FasL pathways. Finally, the immune mediated destruction of hepatocytes, either through soluble or cellular factors, may lead to unmasking of further intracellular autoantigens resulting in a self-enhancing cycle of events.

• #72 Autoimmune Hepatitis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172356-overview

  Autoimmune hepatitis is a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis. Progressive fibrosis may lead to cirrhosis. […] The proposed pathogenesis of autoimmune hepatitis involves the combination of genetic predisposition and environmental triggers. The genetic predisposition may relate to several defects in immunologic control of autoreactivity. An environmental agent may trigger the autoimmune response against liver antigens, causing necroinflammatory liver damage, fibrosis, and, eventually, cirrhosis, if left untreated. […] Genetic susceptibility to developing autoimmune hepatitis has been associated with the human leukocyte antigen (HLA) haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients.

• #73 Pathogenesis of Autoimmune Hepatitis—Cellular and Molecular Mechanisms

  https://www.mdpi.com/1422-0067/22/24/13578

  Pathogenesis of Autoimmune Hepatitis—Cellular and Molecular Mechanisms […] Pediatric autoimmune liver disorders include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is an idiopathic disease characterized by immune-mediated hepatocyte injury associated with the destruction of liver cells, causing inflammation, liver failure, and fibrosis, typically associated with autoantibodies. The etiology of AIH is not entirely unraveled, but evidence supports an intricate interaction among genetic variants, environmental factors, and epigenetic modifications. The pathogenesis of AIH comprises the interaction between specific genetic traits and molecular mimicry for disease development, impaired immunoregulatory mechanisms, including CD4+ T cell population and Treg cells, alongside other contributory roles played by CD8+ cytotoxicity and autoantibody production by B cells. These findings delineate an intricate pathway that includes gene to gene and gene to environment interactions with various drugs, viral infections, and the complex microbiome. Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. The current first-line therapy comprises prednisolone plus azathioprine to induce clinical and biochemical remission. Further understanding of the cellular and molecular mechanisms encountered in AIH may depict their impact on clinical aspects, detect biomarkers, and guide toward novel, effective, and better-targeted therapies with fewer side effects.

• #74 Diagnosis and Management of Autoimmune Hepatitis: Current Status and Future Directions

  https://www.gutnliver.org/journal/view.html?doi=10.5009/gnl15352

  The presence of atypical pANCA has been associated with cirrhosis and relapse after corticosteroid withdrawal in autoimmune hepatitis, but the prognostic implications of atypical pANCA in autoimmune hepatitis have not been sufficiently established to warrant their routine assessment. […] The immunosuppressive actions of azathioprine develop slowly over a 6-week period, and monotherapy with prednisone or prednisolone may have a more rapid action than combination therapy in patients with acute severe disease. […] The calcineurin inhibitors have also been used successfully to salvage patients with corticosteroid-refractory autoimmune hepatitis. […] Most new therapeutic interventions have not moved beyond the theoretical stage in autoimmune hepatitis, but their premise and promise are founded on studies already performed in cell cultures, animal models, or preliminary clinical trials in other immune-mediated diseases.

• #75 Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018909

  These results indicate that the infiltration of TH17 cells likely contribute to hepatic inflammation and disease progression in AIH. […] IL-6, in conjunction with TGF-, promotes the generation of Th17 cells, while IL-17 can also stimulate IL-6 production. […] We hypothesized that there is a positive-feedback loop between Th17 cells and hepatocytes through IL-6 and IL-17 interaction. […] Our study demonstrated that IL-17 increases the production of IL-6 by hepatocytes, which, in turn, further stimulates Th17 cells and provides a positive feedback loop between Th17 cells and hepatocytes exacerbating the inflammatory process. […] In conclusion, Th17 cells and the IL-17 signaling pathway play a critical role in the pathogenesis of AIH. Restoring the imbalance among Th17 cells and Tregs by interrupting interaction between IL-17 and IL-6 may be an effective therapeutic target for autoimmune liver diseases.

• #76 Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018909

  These results indicate that the infiltration of TH17 cells likely contribute to hepatic inflammation and disease progression in AIH. […] IL-6, in conjunction with TGF-, promotes the generation of Th17 cells, while IL-17 can also stimulate IL-6 production. […] We hypothesized that there is a positive-feedback loop between Th17 cells and hepatocytes through IL-6 and IL-17 interaction. […] Our study demonstrated that IL-17 increases the production of IL-6 by hepatocytes, which, in turn, further stimulates Th17 cells and provides a positive feedback loop between Th17 cells and hepatocytes exacerbating the inflammatory process. […] In conclusion, Th17 cells and the IL-17 signaling pathway play a critical role in the pathogenesis of AIH. Restoring the imbalance among Th17 cells and Tregs by interrupting interaction between IL-17 and IL-6 may be an effective therapeutic target for autoimmune liver diseases.

• #77 Immunopathogenesis of Autoimmune Hepatitis | Immunopaedia

  https://www.immunopaedia.org.za/breaking-news/immunopathogenesis-of-autoimmune-hepatitis/

  Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that occurs at any age and mainly affects women. The pathogenesis of AIH is complex and was long unknown. Understanding the immunopathogenesis of AIH is crucial for the treatment of AIH patients and the development of novel AIH therapeutic strategies. […] Despite these effective mechanisms, loss of tolerance in AIH can occur through a combination of genetic predisposition, environmental stimulus and an imbalance in immunological regulatory mechanisms. […] A dynamic balance between proinflammatory Th17 and immunosuppressive Tregs can critically determine the immunopathology of AIH. […] There is a lack of innovative therapies to treat AIH, therefore understanding pathogenic mechanisms is a must, especially the role of Tregs and auto-reactive B cells. Recent case reports have highlighted the potential role of B cell depletion therapy (antiCD20) in refractory cases of AIH. Inhibition of BAFF receptor is a novel therapeutic approach.

• #78 Immunopathogenesis of Autoimmune Hepatitis | Immunopaedia

  https://www.immunopaedia.org.za/breaking-news/immunopathogenesis-of-autoimmune-hepatitis/

  Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that occurs at any age and mainly affects women. The pathogenesis of AIH is complex and was long unknown. Understanding the immunopathogenesis of AIH is crucial for the treatment of AIH patients and the development of novel AIH therapeutic strategies. […] Despite these effective mechanisms, loss of tolerance in AIH can occur through a combination of genetic predisposition, environmental stimulus and an imbalance in immunological regulatory mechanisms. […] A dynamic balance between proinflammatory Th17 and immunosuppressive Tregs can critically determine the immunopathology of AIH. […] There is a lack of innovative therapies to treat AIH, therefore understanding pathogenic mechanisms is a must, especially the role of Tregs and auto-reactive B cells. Recent case reports have highlighted the potential role of B cell depletion therapy (antiCD20) in refractory cases of AIH. Inhibition of BAFF receptor is a novel therapeutic approach.

• #79 Recent advances in the diagnosis and management of autoimmune hepatitis – Polish Archives of Internal Medicine

  https://www.mp.pl/paim/issue/article/16334/

  The therapeutic aim is to achieve remission of the disease at the histological level with as few drug-induced complications as possible. […] The most widely investigated second-line treatment is that with MMF. […] As in other autoimmune and autoinflammatory conditions, B-cell depletion by using rituximab, a monoclonal anti-CD20 antibody, is a promising option for nonresponders to standard therapies. […] The use of tumor necrosis factor (TNF-) inhibitors could have a pathophysiological basis for AIH management given that the TNF pathway has been linked to the pathogenesis of the disease.

• #80 Recent advances in the diagnosis and management of autoimmune hepatitis – Polish Archives of Internal Medicine

  https://www.mp.pl/paim/issue/article/16334/

  We recently found DNA methylation changes in circulating immune cells and at the histological level in patients with AIH, which were associated with disease activity and influenced by immunosuppressive treatment. […] The clinical presentation of AIH in adults is highly heterogeneous. […] Detection of autoantibodies is essential not only for the diagnosis but also for the classification of AIH. […] The presence of soluble liver antigens / liver pancreas antibodies (anti-SLA/LP) was formerly considered a third category of AIH. […] Every patient with suspected AIH should have a liver biopsy performed unless there is a contraindication. […] The International AIH Pathology Group recently issued a consensus statement that proposed a uniform approach to the diagnosis of AIH at the histological level.

• #81 Pathogenesis of autoimmune hepatitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8422914/

  Autoimmune hepatitis (AIH) is a chronic progressive liver disease whose etiology and pathogenesis are not yet clear. It is currently believed that the occurrence of AIH is closely related to genetic susceptibility and immune abnormalities, and other factors such as environment, viral infection and drugs that may cause immune dysfunction. […] Although the exact pathogenesis of AIH is still unclear, there are many theories, and the continuous in-depth research on its pathogenesis has led to development in treatment of AIH. […] The pathogenesis of AIH still needs further research.

• #82 Pathogenesis of autoimmune hepatitis

  https://www.wjgnet.com/1948-5182/full/v13/i8/879.htm

  Autoimmune hepatitis (AIH) is a chronic progressive liver disease whose etiology and pathogenesis are not yet clear. It is currently believed that the occurrence of AIH is closely related to genetic susceptibility and immune abnormalities, and other factors such as environment, viral infection and drugs that may cause immune dysfunction. This article reviews the pathogenesis of AIH and describes the latest research results in the past 5 years. […] Although the exact pathogenesis of AIH is still unclear, there are many theories, and the continuous in-depth research on its pathogenesis has led to development in treatment of AIH. […] The etiology of AIH has not yet been fully clarified. […] Genetic susceptibility, environmental factors (viruses, parasites, pets, etc.), immune system, drugs and biological agents, pregnancy and liver transplantation have been reported to be associated with AIH. The pathogenesis of AIH still needs further research.

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