Aetiopathogenesis of autoimmune hepatitis.
Interface hepatitis, histological hallmark of autoimmune hepatitis (AIH), is a dense portal mononuclear cell infiltrate invading the parenchyma, consisting of CD4 and CD8 T-lymphocytes, monocytes/macrophages and plasma cells. What triggers AIH is unknown, but there is evidence that failure of immune homeostasis plays a permissive role allowing liver autoantigen-specific cells to attack hepatocytes. Damage is likely to be orchestrated by CD4 T-lymphocytes recognizing an autoantigenic liver peptide. For autoimmunity to arise, the peptide, embraced by an HLA class II molecule, must be presented to naïve CD4 T-helper (T(H)0) cells by professional antigen-presenting cells. Once activated, T(H)0 cells can differentiate into T(H)1 cells, which are pivotal to macrophage activation, enhance HLA class I expression, rendering liver cells vulnerable to CD8 T-cell attack, and induce HLA class II expression on hepatocytes; or into T(H)2 cells producing IL-4, IL-10 and IL-13, cytokines favouring autoantibody production by B-lymphocytes. Autoantigen recognition is tightly controlled by regulatory mechanisms, such as those exerted by CD4+CD25+ regulatory T-cells (T-regs). Numerical and functional T-reg impairment characterizes AIH, particularly during active disease. Advances in the study of autoreactive T-cells stem mostly from AIH type 2, where the main autoantigen, CYP2D6, is known enabling characterization of antigen-specific immune responses. Monocyte involvement in the autoimmune liver attack has been recently reported.
Longhi
Maria Serena
MS
Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, UK.
Ma
Yun
Y
Mieli-Vergani
Giorgina
G
Vergani
Diego
D
D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D019693:Hepatitis, Autoimmune / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D018716:Molecular Mimicry; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D019389:Cytochrome P-450 CYP2D6