Pathogenesis of autoimmune hepatitis
Section snippets
Cellular immunity
Examination of the liver tissue reveals a dramatic picture. A multitude of mononuclear cells, lymphocytes, plasma cells, and macrophages infiltrate the portal tract, invade the adjacent parenchyma, and surround dying hepatocytes. This scenario, defined by histologists as interface hepatitis, first suggested that autoaggressive cellular immunity was involved in the pathogenesis of the disease [1], [2]. Immunocytochemical studies have identified the phenotype of the infiltrating cells. T
Humoral immunity and T and B Cell Co-operation
Titers of antibodies to the liver specific lipoprotein (LSP), a macromolecular complex present on the hepatocyte membrane, and to its well-characterized component, asialoglycoprotein receptor (ASGPR), correlate with the biochemical and histologic severity of AIH [16], [17]. Recently, antibodies to alcohol dehydrogenase (ADH), a second well-defined component of LSP, have been described in patients with AIH [18]. Immunofluorescence studies on monodispersed suspensions of liver cells obtained from
Possible routes to autoimmunity
The immune system has evolved to discriminate between endogenous or self tissues and exogenous and neoplastic components, collectively termed nonself. A dominant selective pressure in this process has been the threat to self-integrity posed by infectious pathogens. The virtually infinite antigenic variety of pathogens to which the immune system must respond has resulted in an innate set of responses that allow the triggering of immunity to commonly encountered pathogens. An adaptive system has
Antibodies to liver and kidney microsome type 1 and molecular mimicry
Type 2 AIH is characterized by seropositivity for antibodies to liver and kidney microsome type 1 (anti-LKM1) [35]. The target of this reactivity is cytochrome P450 2D6 (CYP2D6)—a member of the hepatic P450 enzyme family [36]. Because of the strong association between anti-LKM1 and type 2 AIH and because of a recent report showing surface expression of CYP2D6 on hepatocytes (rendering them amenable to recognition by these antibodies), anti-LKM1 are thought to be involved in the pathogenesis of
Multiple autoimmunity in autoimmune hepatitis
Type 2 AIH frequently coexists with other autoimmune diseases, particularly type 1 diabetes, Addison's disease, hypoparathyroidism, and autoimmune thyroiditis [47]. The authors have shown cross-reactive anti-LKM1 responses among CYP2D6321-351, the second most frequently recognized epitope of CYP2D6, and structurally similar regions of carboxypeptidase H, an autoantigen in type 1 diabetes, and 21-hydroxylase, the major autoantigen in Addison's disease [48]. The authors propose that autoimmunity
Summary
Autoimmune hepatitis is initiated by CD4 T cells that recognize self-antigen. The effector cells differentiate into functional phenotypes according to cytokines in the microenvironment and the nature of the triggering antigen. Hepatocytes can express class II molecules and present antigenic peptides through a bystander mechanism. NKT cells reside in the normal liver but may be involved in liver cell damage possibly through the expression of Fas ligand. Autoantibodies may also participate in the
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