Mechanisms of alcohol liver damage: aldehydes, scavenger receptors, and autoimmunity.
While most of the investigations into the causative events in the development of alcoholic liver disease (ALD) have been focused on multiple factors, increasing interest has centered around the possible role of immune mechanisms in the pathogenesis and perpetuation of ALD. This is because many of the clinical features of ALD suggest that immune effector mechanisms may be contributing to liver tissue damage, as evidenced by the detection of circulating autoantibodies, and the presence of CD4+ and CD8+ lymphoid cells in the livers of patients with ALD. One mechanism that has been associated with the development of autoimmune responses is the modification (haptenation or adduction) of liver proteins with aldehydes or other products of oxidative stress. This is because it has been shown that these adducted proteins can induce specific immune responses, to the adduct, the adduct plus protein (conformational antigens), as well as the unmodified parts of the protein. More importantly, it is possible to demonstrate that adducted self-proteins can induce reactivity to the normal self-protein and thereby induce autoimmune responses. Therefore, it is the purpose of this manuscript to outline the mechanism(s) by which these modified self proteins can induce autoimmune reactivity, and thus play a role in the development and/or progression of ALD.
Duryee
Michael J
MJ
University of Nebraska Medical Center, Department of Internal Medicine, 988090 Nebraska Medical Center, Omaha, NE 68198-8090, USA.
Willis
Monte S
MS
Freeman
Thomas L
TL
Kuszynski
Charles A
CA
Tuma
Dean J
DJ
Klassen
Lynell W
LW
Thiele
Geoffrey M
GM
D000079:Acetaldehyde / Q000737:chemistry; D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000378:metabolism; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016923:Cell Death; D018450:Disease Progression; D006241:Haptens / Q000737:chemistry; D006505:Hepatitis / Q000473:pathology; D006801:Humans; D007107:Immune System / Q000473:pathology; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008315:Malondialdehyde / Q000737:chemistry; D009336:Necrosis; D018384:Oxidative Stress; D051116:Receptors, Scavenger / Q000378:metabolism*; D017634:Self Tolerance
D000447:Aldehydes; D006241:Haptens; D008077:Lipoproteins, LDL; D051116:Receptors, Scavenger; C099252:oxidized low density lipoprotein; D008315:Malondialdehyde; D000079:Acetaldehyde; C027576:4-hydroxy-2-nonenal