The lymphoid liver: considerations on pathways to autoimmune injury.
Immunologic injury in the liver involves immigrant T and B lymphocytes and a resident lymphoid population that comprises distinct lymphocytic cells and accessory cells. The forerunner to autoimmunity is breaching of natural self-tolerance and hence the disruption of a fundamental property of the immune system. Such breaching occurs by processes that include inflammatory activation of immunocytes and macrophages, spillage of intracellular constituents, and epitope mimicry by constituents of microorganisms, with these acting on a genetically conditional phenotype; compounding factors include aberrations of apoptosis, whether insufficient or excess. The downstream end requires specifically directed inflammatory leukocyte traffic as an essential component of autoimmune expressions in the liver. The culmination is an orchestrated attack on hepatocytes or biliary epithelial cells by multiple effector pathways. Progress in type 1 autoimmune hepatitis still requires knowledge of a disease-specific autoantigen(s) involved in T-cell reactivity, although such knowledge in type 2 autoimmune hepatitis, in which the known autoantigen is cytochrome P4502D6, has not yet been integrated into a clearly defined scheme of pathogenesis. For PBC there has been a very promising amalgamation of molecular knowledge of the mitochondrial autoantigens. Future insights require deeper analysis of molecular, genetic, macroenvironmental, and microenvironmental elements in predisposition.
Kita
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Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis School of Medicine, Davis, California 95616, USA.
Mackay
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Van De Water
J
J
Gershwin
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ME
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000209:etiology*; D002465:Cell Movement; D015209:Cholangitis, Sclerosing / Q000209:etiology; D019693:Hepatitis, Autoimmune / Q000209:etiology; D006801:Humans; D007108:Immune Tolerance; D007962:Leukocytes / Q000502:physiology; D008099:Liver / Q000276:immunology; D008105:Liver Cirrhosis, Biliary / Q000209:etiology; D008107:Liver Diseases / Q000209:etiology*; D008214:Lymphocytes / Q000502:physiology; D013234:Stem Cells / Q000502:physiology