Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management

Abstract

Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver, and of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating c-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4? and CD8? T cells are involved together with effector responses mediated by NK cells, cd T cells, and macrophages. A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis.

Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis

“…In contrast, our mice develop T cell-driven chronic liver damage, hence reproducing the immunopathological changes of human AIH more closely (35). An additional parallelism between the model described in the present study and the human condition is the abundance of CD8 T cells with an effector phenotype infiltrating the liver (35). Also, as observed in human AIH, AAV-IL12-treated mice exhibit augmented B cells in the liver, a finding that in the patients has been linked to the presence of hypergammaglobulinemia (2).…”

“…In other instances of immunemediated liver injury, such as Con A-or a-galactosylceramideinduced hepatitis, NKT cells were shown to be essential pathogenic mediators, but these are models of acute liver injury rather than of chronic hepatitis (8,34). In contrast, our mice develop T cell-driven chronic liver damage, hence reproducing the immunopathological changes of human AIH more closely (35). An additional parallelism between the model described in the present study and the human condition is the abundance of CD8 T cells with an effector phenotype infiltrating the liver (35).…”

“…PD-1/PD-L1 interaction conveys negative signals to T cells resulting in the blockade of their effector functions. In the liver of our mouse model, as in the liver of AIH patients, the expression of both PD-1 and PD-L1 and the levels of IL-10 and TGF-b are higher than in controls (35); however, liver damage occurs, thus indicating that these immunomodulatory mechanisms do not suffice to halt T cell-mediated hepatocyte injury. Our findings in the present murine model of AIH imply, however, that PD1/PD-L1 interaction significantly contributes to ameliorating immune-mediated liver damage, as its blockade clearly exacerbates the disease.…”

IFN-γ siRNA Effectively Knocked Down IFN-γ Gene Expression and Reduced Cytokine Secretion in Peripheral Blood Mononuclear Cells of Patients with Autoimmune Hepatitis

“…As mentioned above, the remission of more than 80% AIH patients achieves by receiving prednisolone and azathioprine and corticosteroid therapy. These immunosuppressive drugs have many adverse effects in long-term use that is serious for individuals (13).…”

Hepatitis autoinmune precedida por infección aguda por citomegalovirus en una mujer inmunocompetente

“…En relación con el papel viral, la teoría más plausible es la del mimetismo molecular, según la cual algunos antígenos víricos que presentan cierta homología con los autoantígenos producirían una reacción humoral cruzada, iniciando la producción de autoanticuerpos que conduce al daño tisular. A su vez, el ambiente proinflamatorio generado por el virus (mediado por la liberación de citoquinas), activaría a las células T autorreactivas, modificando el procesamiento y presentación de autoantígenos, jugando un papel crítico a la hora de perpetuar la generación de autoanticuerpos 7,8 . Los virus que con mayor frecuencia desencadenan HAI corresponden a la familia de los herpesvirus y son el VHA 9 , seguido del VHB y el VHC.…”