title: The role of natural killer (NK) and NK T cells in the loss of tolerance in murine primary biliary cirrhosis.
abstract: One of the major obstacles in dissecting the mechanism of pathology in human primary biliary cirrhosis (PBC) has been the absence of animal models. Our laboratory has focused on a model in which mice, following immunization with a xenobiotic chemical mimic of the immunodominant autoepitope of the E2 component of pyruvate dehydrogenase complex (PDC-E2), develop autoimmune cholangitis. In particular, following immunization with 2-octynoic acid (a synthetic chemical mimic of lipoic acid-lysine located within the inner domain of PDC-E2) coupled to bovine serum albumin (BSA), several strains of mice develop typical anti-mitochondrial autoantibodies and portal inflammation. The role of innate immune effector cells, such as natural killer (NK) cells and that NK T cells, was studied in this model based on the hypothesis that early events during immunization play an important role in the breakdown of tolerance. We report herein that, following in-vivo depletion of NK and NK T cells, there is a marked suppression of anti-mitochondrial autoantibodies and cytokine production from autoreactive T cells. However, there was no change in the clinical pathology of portal inflammation compared to controls. These data support the hypothesis that there are probably multiple steps in the natural history of PBC, including a role of NK and NK T cells in initiating the breakdown of tolerance. However, the data suggest that adaptive autoimmune effector mechanisms are required for the progression of clinical disease.
authors.affiliation: Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shimoda
authors.forename: K
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: K
authors.initials: K
authors.lastname: Kikuchi
authors.forename: K
authors.initials: K
authors.lastname: Harada
authors.forename: Y
authors.initials: Y
authors.lastname: Nakanuma
authors.forename: M
authors.initials: M
authors.lastname: Nakamura
authors.forename: H
authors.initials: H
authors.lastname: Ishibashi
authors.forename: S
authors.initials: S
authors.lastname: Hisamoto
authors.forename: H
authors.initials: H
authors.lastname: Niiro
authors.forename: P S C
authors.initials: PS
authors.lastname: Leung
authors.forename: A A
authors.initials: AA
authors.lastname: Ansari
authors.forename: M E
authors.initials: ME
authors.lastname: Gershwin
authors.forename: K
authors.initials: K
authors.lastname: Akashi
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000276:immunology; D040761:Biomimetic Materials / Q000737:chemistry; D002417:Cattle; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance; D007114:Immunization; D016056:Immunodominant Epitopes / Q000737:chemistry; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000737:chemistry; D008063:Thioctic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D016056:Immunodominant Epitopes; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D012710:Serum Albumin, Bovine; D008063:Thioctic Acid; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C494878:Dlat protein, mouse